Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
AI-Native Drug Discovery Landscape 2026 – How LPBI Group Differentiates in the New Era of Foundation Models
Curators: Aviva Lev-Ari, PhD, RN with Grok Assistence
As the race to build powerful biology foundation models intensifies, several well-funded AI-native companies have emerged with ambitious platforms for protein design, small-molecule generation, and multimodal drug discovery. While these companies bring strong technical capabilities, LPBI Group occupies a distinct and complementary position in the ecosystem.
Key AI-Native Players (2026)
Competitive Landscape Table for AI-Native in Drug Discovery
Company
Focus
Stage
LPBI Differentiation
Isomorphic Labs (DeepMind)
Protein/small molecule design using AI
Advanced (AlphaFold3 based)
LPBI offers curated multimodal training data + COM methodology (they need high-quality data to train/validate)
EvolutionaryScale
Protein design (ESM models)
Early commercial
LPBI’s strength is in clinical/therapeutic context + mechanism-of-action curation across full disease spectrum
Chai Discovery
Multimodal AI for drug discovery
Early
LPBI provides the upstream high-provenance corpus + ontology they would need for better results
Recursion Pharma
Phenotypic screening + AI
Clinical stage
LPBI’s expert-curated literature + images + COM complements their wet-lab focus
Generative AI for protein design & therapeutic optimization
Early-stage
LPBI supplies the high-provenance, expert-curated multimodal corpus and COM Tool Factory that significantly enhances model accuracy and reduces failure rates in downstream development
How LPBI Group Differentiates
LPBI Group does not compete directly in building foundation models. Instead, we provide the critical upstream layer these companies and hyperscalers urgently need:
A 9 GB private multimodal corpus of expert-curated scientific content (6,290+ articles, 48 e-Books, 7,500+ images, 300+ podcasts)
The 17-part Composition of Methods (COM) Tool Factory, including AJAUS (autonomous 24/7 refresh) and Rosetta Stone Ontology (causal mapping)
15 Subject Matter Small Language Models (SLMs) ready for concatenation into proprietary LLMs and MFMH
Proven track record of 4–5×+ uplift in novel causal relationship extraction when combined with frontier models
Strategic Positioning
While AI-native startups excel at model architecture and computation, they still face the persistent bottleneck of high-quality, causally structured, provenance-rich training data. LPBI Group’s vertically integrated assets and methodology offer a defensible moat and a true “own-both” advantage when partnered with hyperscalers or pharma companies.
This complementary role positions LPBI Group as the ideal upstream partner for the next generation of domain-aware AI in Health.
AlignedHQ.ai as Partner vs. Insilico Medicine
AlignedHQ.ai is a strong potential partner.
Why?
They are AI-native focused on protein design and generative models — directly complementary to LPBI’s strengths in curated biomedical literature, mechanism-of-action, and multimodal data.
They would benefit enormously from access to LPBI’s high-quality training data and COM methodology.
Partnership model: They use LPBI data (licensed) + Grok 5 / SpaceXAI compute and frontier models → Co-develop specific therapeutic pipelines.
Insilico Medicine is also a good candidate but slightly less ideal than AlignedHQ for early partnership because:
Insilico is more advanced clinically (has candidates in trials) and may want more control.
AlignedHQ appears earlier-stage and more open to collaboration.
Recommendation: Start with AlignedHQ.ai as a proof-of-concept partner (easier entry, high complementarity). Use success there to approach Insilico and others from a position of strength.
Where does AlignedHQ.ai’s Domain Knowledge in Medicine Come From?
From public information:
Primarily from public + licensed datasets (PDB, UniProt, scientific literature, clinical trial data, etc.).
They rely heavily on large-scale public biomedical databases and pre-trained models (e.g., AlphaFold derivatives).
Like most AI-native drug discovery companies, they have limited proprietary clinical/therapeutic context compared to LPBI’s expert-curated, mechanism-rich corpus.
Their domain knowledge is model-derived rather than expert-curated at source.
This is LPBI’s Core Delta: AlignedHQ (and similar companies) excel at model architecture and generation but lack the deep, traceable, expert-validated biomedical knowledge that LPBI has built over 14+ years. This is why access to LPBI’s portfolio would be highly valuable to them.
The following remembrances of American Association of Cancer Research (AACR) prominent member who have recently passed in 2026 is given below. Each have contributed seminal research and discovery in the field of cancer biology and cancer risk. In many cases, their discoveries transformed the way we understand and treat cancer. A separate In Memoriam for Nobel Leaureatte Dr. J. Michael Bishop will be given in a separate post.
Joseph F. Fraumeni, Jr., MD, FAACR, a renowned cancer epidemiologist, a Fellow of the AACR Academy, and a former member of the AACR Board of Directors, died June 22, 2026, at the age of 93. A career researcher and leader at the National Cancer Institute, Fraumeni was a co-discoverer of the genetic condition now known as the Li-Fraumeni syndrome and launched the U.S. Atlas of Cancer Mortality, which mapped geographic variations in cancer.Born April 1, 1933, in Boston, Fraumeni earned a bachelor’s degree from Harvard College, a medical degree from Duke University School of Medicine, and a master of science in epidemiology from the Harvard University School of Public Health. He completed medical residencies at Johns Hopkins Hospital and the Memorial Sloan-Kettering Cancer Center. A member of the AACR since 1968, Fraumeni served on the AACR’s Board of Directors from 1983 to 1986. He also served the AACR as an assistant editor, senior editor, and editorial board member for Cancer Epidemiology, Biomarkers & Prevention and an assistant editor for Cancer Research. The AACR recognized him with the AACR-American Cancer Society Award for Research Excellence in Epidemiology and Prevention in 1993 and the AACR Award for Lifetime Achievement in Cancer Research in 2009. He was inducted as a member of the inaugural class of Fellows of the AACR Academy in 2013. Fraumeni was a fellow of the American College of Physicians, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences, and a member of the Institute of Medicine, the Association of American Physicians, and the National Academy of Sciences.
In 1962, Fraumeni joined the Epidemiology Branch of the National Cancer Institute (NCI) as a commissioned officer in the U.S. Public Health Service (USPHS). He went on to hold several leadership positions at the NCI, including posts as head of the Ecology Studies Section, chief of the Environmental Epidemiology Branch, director of the Epidemiology and Biostatistics Program, and founding director of the Division of Cancer Epidemiology and GeneticsHe retired from the USPHS in 1999 with the rank of rear admiral and assistant surgeon general. When he retired from NCI in 2017, he was named Scientist Emeritus. He authored or co-authored more than 900 scientific publications.
His research focused the epidemiology of high cancer risk populations and, in 1969, led him to discover a familial syndrome of early-onset cancers of the breast, brain, and other malignancies known as Li-Fraumeni Syndrome. Li-Fraumeni Sydrome is characterized by inherited mutations in the p53 tumor suppressor gene.
Li-Fraumeni Syndrome
from Cleveland Clinic: Li-Fraumeni syndrome is a rare genetic disorder that increases the risk you and your family members will develop cancer. Everyone with this condition has a 90% chance of developing one or more types of cancer by age 60. About half develop cancer before they turn 40. Females with Li-Fraumeni syndrome almost always develop breast cancer.
Below is the original reference published with his colleague the late Dr, Federick Li. Thier work together over the years helped develop the discovery of cancer susceptiblitiy genes and the importance of mutations of these genes linked to increased risk of developing cancer.
Li FP, Fraumeni JF Jr. 1969. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71: 747–752.
Four families were identified in which a pair of children had soft-tissue sarcomas: three sets of sibs and one set of cousins. One parent of each affected child developed cancer; carcinoma of the breast occurred in three mothers under 30 years of age. Other young adults in these families had a high frequency of cancer, with no evidence of underlying genetic disorders known to carry a high risk of neoplasia. The increased familial susceptibility to cancer was manifested not only by the large number of members affected but by a seeming excess of multiple primary neoplasms.
It wasn’t until the 1990’s that Malkin et al. that germline mutations in TP53 were associated with this disease
Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al. 1990. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233–1238.
A similar syndrome named Lynch syndrome also gave rise to early increased risk of multiple cancers but due to germline mutations in mismatch repair genes like MLH1, MSH2, MSH6, or PMS2.
Lynch HT, Mulcahy GM, Harris RE, Guirgis HA, Lynch JF. 1978. Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer 41: 2055–2064.
Pierre Chambon, MD, FAACR, a Fellow of the AACR Academy who was a pioneer in the structure and expression of genes, died May 5, 2026, at the age of 95. Chambon’s early work contributed to the discovery of PolyADPribose, the discovery of multiple RNA polymerases, major contributions to the elucidation of chromatin structure, and the discovery of animal split genes. Later work included the discovery of multiple promoter elements and their cognate factors. His research on nuclear receptors has had a marked influence on the understanding of signal transduction and endocrinology in vertebrates.
Born February 7, 1931, in Mulhouse, France, Chambon received his medical degree from the University of Strasbourg in 1958. He joined the university as a research associate, becoming an associate professor in 1962 and professor of biochemistry in 1968. He founded the Institute for Genetics and Cellular and Molecular Biology in 1994 and served as its director until 2002. He then founded the Mouse Clinical Institute and served as director until 2006. He held the chair of molecular genetics at the Collège de France from 1993 to 2003 and served as chair of molecular genetics and biology at the University of Strasbourg Institute for Advanced Study from 2012 to 2021. Chambon was elected to the French Academy of Sciences in1985, the same year in which he was elected a foreign member of both the U.S. National Academy of Sciences and the American Academy of Arts and Sciences.
Juliet M. Daniel, PhD
Juliet M. Daniel, PhD, a cell biologist who was a distinguished university professor at McMaster University in Hamilton, Ontario, and member of AACR since 2002, died April 28, 2026. She was 61 years of age. Noted for her work on genetic risk factors for breast cancer, Daniel discovered and gave the name “Kaiso” to a gene associated with triple negative breast cancer in women of African descent. Born in Barbados in 1964, Daniel obtained a bachelor’s degree in life sciences from Queen’s University in Kingston, Ontario, in 1987 and a doctorate in microbiology from University of British Columbia in Vancouver in 1993. She conducted postdoctoral research at St. Jude Children’s Research Hospital in Memphis and Vanderbilt University in Nashville. She joined McMaster as an assistant professor in 1999, the first black woman to become a member of the Faculty of Science. She was promoted to associate professor in 2005 and professor in 2012. Daniel was appointed associate dean of research and external relations for the Faculty of Science on an acting basis in 2020 and permanently in 2021. She was named strategic advisor to the university president for the Canada-Caribbean Institute (CCI) at McMaster in 2024. She was named a distinguished university professor, the highest faculty honor, in 2025. Among many other honors, she was elected a fellow of the Canadian Academy of Health Sciences in 2025, received the inaugural Canadian Cancer Society Inclusive Excellence Prize in Cancer Research in 2020, and was awarded an honorary doctorate in science by the University of the West Indies in 2021.
Philip S. Low, PhD
Philip S. Low, PhD, the Ralph C. Corley distinguished professor of chemistry at Purdue University, an inventor and entrepreneur with more than 100 patents to his credit, and an emeritus member of AACR, died March 4, 2026, at the age of 78. He also served as Purdue’s Presidential Scholar for Drug Discovery and was for a time as director of the university’s Center for Drug Discovery. Low held more than 100 U.S.-issued patents through Purdue Innovates and is listed on 600 U.S. and international patents and 145 invention disclosures. He founded seven companies based on based on work conducted at Purdue, one of which, Endocyte Inc., was sold to Novartis in 2018. Born in Ames, Iowa, in 1947, Low earned a bachelor’s degree in chemistry from Brigham Young University in 1971 and a doctorate in biochemistry from the University of California, San Diego, in 1975. He joined the Purdue University faculty in 1976. An AACR member since 2005, Low received the AACR Award for Outstanding Achievement in Chemistry in Cancer Research in 2015 in recognition of his research on low molecular weight ligand-targeted therapeutic and imaging agents. In the same year, he also received the American Chemical Society (ACS) George & Christine Sosnovsky Award for Cancer Research and was elected to the National Academy of Inventors. In August 2025, Low was named the recipient of the ACS Alfred Burger Award in Medicinal Chemistry for 2026. He also received the Order of the Griffin and the Morrill Award from Purdue.
In Memoriam: Professor Yitzhak Apeloig, President and Distinguised Professor of the Technion
Reporters: Aviva Lev-Ari, PhD, RN and Stephen J. Williams, Ph.D.
From the Technion:
The Technion community mourns the passing of Distinguished Professor Yitzhak Apeloig (1944–2026), president of the Technion from 2001 to 2009 and one of Israel’s most distinguished chemists.
A pioneer in computational chemistry and organosilicon compounds, Prof. Apeloig made groundbreaking scientific contributions while mentoring generations of researchers and helping position the Technion as a global leader in science and technology.
During his presidency, he expanded interdisciplinary research, strengthened international partnerships, increased investment in research infrastructure and scholarships, and advanced collaboration between engineering, medicine, and the humanities.“Prof. Apeloig led the Technion with quiet confidence and steadfast leadership,” said Technion President Prof. Uri Sivan. “His years in office were marked by exceptional academic development and a profound impact on the State of Israel and beyond.”
The Technion was his home and family. He will be deeply missed. May his memory be a blessing.
Distinguished Professor Yitzhak Apeloig (1944–2026), president of the Technion from 2001 to 2009 and one of Israel’s most distinguished chemists
A brief synopsis of Dr. Apeloig’s scientific achievements and contributions toward the field of chemistry:
1. Pioneering Computational Quantum Chemistry
In the 1970s, Apeloig was one of the first experimental chemists in the world to recognize the immense potential of using quantum theory and computational models to predict molecular characteristics.
The “First Calculate, Then Synthesize” Philosophy: He pioneered a paradigm shift in organic chemistry by using quantum-mechanical calculations to predict whether a novel molecule could exist and what its lifespan would be before attempting physical synthesis in the laboratory.
He was unique for his time in requiring his students to master both computational modeling and physical laboratory experimentation rather than separating the disciplines.
2. Breakthroughs in Organosilicon Chemistry
Before Apeloig’s work, much of the scientific community believed that silicon could not easily form stable multiple bonds (such as $Si=Si$ or $Si=C$ double bonds) in the way carbon does. Apeloig revolutionized the field of organosilicon chemistry:
Low-Coordination Silicon Compounds: He successfully used computational tools combined with experimental testing to predict, isolate, and understand highly reactive, low-coordination silicon species. This included landmark research into multiply-bonded silicon compounds, silyl radicals, silyl anions, silylenes, and metallosilane reagents.
Silicone and Materials Science: His structural insights fundamentally advanced the molecular understanding of silicon polymers and siloxanes, which heavily influenced the development of advanced moulding materials, rubbers, and photosensitive materials used in lithography.
3. Discovery of Reactive Intermediates
During his early career and PhD research, he focused heavily on physical organic chemistry and organic reaction mechanisms:
He was the first to experimentally demonstrate that a vinyl cation holds a linear geometry around its carbocationic center.
His extensive work mapping out short-lived, highly reactive intermediates (like carbenium ions and strained molecules) provided the foundational mechanics for how complex organic reactions occur.
Major Recognitions
For these definitive contributions to computational and silicon chemistry, Apeloig was awarded some of the highest honors in the discipline:
The Schrödinger Medal (2021): Awarded by the World Association of Theoretical and Computational Chemists (WATOC) for his seminal contributions to theoretical chemistry.
The ACS Frederic Stanley Kipping Award in Silicon Chemistry (2010): The premier international award recognizing advancements in the study of silicon.
The Wacker Silicone Award (2007) and the Israel Chemical Society Gold Medal (2017).
The seminal publications that define his academic footprint include:
1. Foundational Computational and Structural Chemistry
During the mid-1970s and 1980s, Apeloig co-authored several massive, highly cited studies establishing the rules of computational molecular architecture, specifically challenging traditional rules of carbon and silicon bonding.
“Stabilization of planar tetracoordinate carbon”
Journal of the American Chemical Society (1976)
Co-authors: J. B. Collins, J. D. Dill, E. D. Jemmis, P. v. R. Schleyer, R. Seeger, J. A. Pople
Impact: A true milestone in structural chemistry that theoretically demonstrated how specific substitution patterns could stabilize a planar geometry around a carbon atom, defying the standard tetrahedral configuration.
“A theoretical survey of unsaturated or multiply bonded and divalent silicon compounds. Comparison with carbon analogs”
Journal of the American Chemical Society (1986)
Co-authors: B. T. Luke, J. A. Pople, M. B. Krogh-Jespersen, M. Karni, J. Chandrasekhar, P. v. R. Schleyer
Impact: A definitive ab initio survey that comprehensively mapped out the differences between carbon and silicon multiple bonds, predicting the stability and reaction behaviors of transient silicon chemical species.
2. High-Impact Silicon and Stable Carbene Analogs
In the 1990s and 2000s, Apeloig focused on predicting and identifying highly sought-after reactive intermediates—particularly “impossible” double bonds and carbenes.
“On the Question of Stability, Conjugation, and ‘Aromaticity’ in Imidazol-2-ylidenes and Their Silicon Analogs”
Journal of the American Chemical Society (1996)
Co-authors: C. Heinemann, T. Müller, H. Schwarz
Impact: Heavily cited paper evaluating the electronic properties, structural stability, and aromaticity of N-heterocyclic carbenes (NHCs) versus their heavier silicon counterparts (silylenes).
“Substituent effects on the geometries and energies of the silicon-silicon double bond”
Journal of the American Chemical Society (1990)
Co-author: M. Karni
Impact: This study mapped how changing the attached chemical groups altered the trans-bending and bond lengths of $Si=Si$ double bonds, establishing a predictive guide for experimentalists trying to isolate stable disilenes.
3. Definitive Academic Reviews and Reference Books
Beyond standalone journal entries, Apeloig is globally recognized for editing the foundational texts that summarized the state of organosilicon chemistry for generations of scientists.
“The Chemistry of Organic Silicon Compounds” (Volumes 1, 2, and 3)
Co-edited with: Zvi Rappoport (Published by John Wiley & Sons, beginning in 1989)
Impact: Apeloig authored critical chapters, such as “Theoretical Aspects of Organosilicon Compounds,” within these volumes. This multi-book compendium serves as the literal “bible” for researchers studying silicon polymers, reactive silicon intermediates, and silicon-based material sciences.
Live Notes from JP Morgan Healthcare Conference Virtual Endpoints Preview: January 8-9 2024
Reporter: Stephen J. Williams, Ph.D.
Endpoints at #JPM24 | Primed to unlock biopharma’s next dealmaking wave
Endpoints at JP Morgan Healthcare Conference
January 8-9 | San Francisco, CA80 Mission St, San Francisco, CA
An oasis has emerged in the biopharma money desert as backers look to replenish capital — still, uncertainty remains on whether it’s a mirage or the much needed dealmaking bump the industry needs. Yet spirits run high as JPM24 marks the triumphant return of inking strategic alliances and peering into the industry crystal ball — while keeping an eye out for some major M&A.
We’re back live from San Francisco for JPM Monday and Tuesday — our calendar of can’t-miss panels and fireside chats will feature prominent biopharma leaders to watch. The Endpoints Hub provides the ultimate coworking space with everything you need — 1:1 and group meeting spots plus guest pass capabilities and more. Join us in-person at the Endpoints Hub or watch online to stay plugged into all the action.
8 JAN
Welcome remarks
8:05 AM – 8:25 AM PST
Pfizer vet Mikael Dolsten has some thoughts on Big Pharma R&D
Endpoints News founding editor John Carroll will sit down with longtime Pfizer CSO Mikael Dolsten to talk about Pfizer’s pipeline, what he’s learned on the job about preclinical research and development and what’s ahead for the pharma giant in drug development and deals.
Mikael Dolsten
Chief Scientific Officer, President, Pfizer Research & Development
Pfizer
Pfizer Mikael Dolsten: Pfizer produced a series of AI generated molecules with new properties. Sees rapid adoption of AI in the area of drug discovery and molecular design.
8:25 AM – 9:05 AM PST
What pharma wants: The industry’s dealmakers look ahead at 2024
The drug industry’s appetite for new assets hasn’t slowed down. Top business development execs will give their outlook on the year, what they’re looking for and how they see the market.
Glenn Hunzinger
Pharmaceutical & Life Sciences Consulting Solutions Leader
PwC US
Rachna Khosla
SVP, Head of Business Development
Amgen
James Sabry
Global Head of Pharma Partnering
Roche
Devang Bhuva
SVP, Corporate Development
Gilead Sciences, Inc.
Endpoints News
Dealmaking panel
Glenn Hunzinger: if you do not have a GLP1 will have a tough time getting a good market price for your company; capital markets are not where they want to be; sees a tough deal making climate like last year. The problem with many biotech companies are they are coming earlier to the venture capital because of greater funding needs and so it is imperative that they articulate the potential of their company in scientific detail
Rachna Khosla: Make sure your investors are not just CAPITAL PARTNERS but use their expertise and involve them in development issues you may have, especially ones that a young firm will face. The problem is most investments assume what the future looks like (for example how antibody drug conjugates, once a field left for dead, has been rejuvenated because of advances in chemistry).
James Sabry: noted that cardiac and metabolic drugs are now at the focus of many investors, especially with the new anti-obesity drugs on market
Devang Bhuva: Most deals we see start as collaborations or partnerships. You want to involve an alliance management team early in the deal making process. This process could take years.
9:05 AM – 9:20 AM PST
The IPO: How Apogee Therapeutics went public in the most challenging market in years
Not many biotechs went public in 2023. And of those that did, not many have had a great time of it. Apogee is the exception and our panel will offer a behind-the-scenes look at their decision to enter the market and what life is like as a young public company.
Michael Henderson
CEO
Apogee Therapeutics
Kyle LaHucik
MODERATOR
Senior Reporter
Endpoints News
Michael Henderson: Not many biotech IPOs deals happened in 2023. Michael feels it is because too many biotechs focused on building platforms, which was a hard sell in 2023. He felt not many biotechs had clear milestones and investors wanted a clear primary validated target. He said many biotech startups are in a funding crunch and most need at least $440M on their balance sheet to get to 2026.
9:50 AM – 10:10 AM PST
Top predictions for biotech in 2024
Catalent CEO Alessandro Maselli will be back at the big JPM healthcare confab to talk with Endpoints News founder John Carroll about their top predictions of what’s coming up for the biotech industry in 2024. The stakes couldn’t be higher as the industry grapples with headwinds and new opportunities in a gale of market forces. Two top observers share their thoughts on the year ahead.
Alessandro Maselli
President & CEO
Catalent
10:15 AM – 10:35 AM PST
Innovation at a crossroads: Keys to unlocking the value of science and technology
The industry has long discussed the promise of technology and the acceleration it provides in scientific advancement and across the industry value chain. However, the promise of its impact has yet to fully be realized. This discussion will outline the keys to unleashing this promise and the implications and actions to be taken by the biopharmaceutical companies across the industry.
Ray Pressburger
North America Life Sciences Industry Lead & Global Life Sciences Strategy Lead
Accenture
SPONSORED BY
10:35 AM – 11:05 AM PST
Activism and Investing: In conversation with Elliott Investment Management’s Marc Steinberg
Elliott has been behind many of 2023’s highest-profile healthcare investments, including multiple activist engagements and taking Syneos Health private. What has made large healthcare companies such interesting investment opportunities for firms like Elliott? What’s Elliott’s investing strategy in healthcare? And what should companies expect when an activist calls?
Marc Steinberg
Senior Portfolio Manager
Elliott Investment Management
Andrew Dunn
MODERATOR
Biopharma Correspondent
Endpoints News
11:05 AM – 11:35 AM PST
Creating ROI from AI
AI is predicted to transform the way drugs are made, from discovery to clinical trials to market. But beyond the initial hype and early adoption, where has AI made meaningful contributions to R&D? How does it help drug developers advance science? Endpoints publisher Arsalan Arif is convening a panel of leading experts to discuss the state of AI in the pharmaceutical landscape and the outlook for 2024. How does AI impact the drug pipeline, from the early steps of discovery to reducing trial failure rate?
Thomas Clozel
Co-Founder & CEO
Owkin
Venkat Sethuraman
SVP, Global Biometrics & Data Sciences
Bristol Myers Squibb
Frank O. Nestle
Global Head of Research & Chief Scientific Officer
Sanofi
Matthias Evers
Chief Business Officer
Evotec
Arsalan Arif
MODERATOR
Founder & Publisher
Endpoints News
SPONSORED BY
11:35 AM – 12:00 PM PST
Biopharma’s dealmaker: Behind the scenes with Centerview Partners co-president Eric Tokat
Almost every major biopharma deal in 2023 had Centerview’s name attached to it. And much of the time, Eric Tokat was the banker making those deals happen. Hear his outlook for 2024, how transactions are getting done and what’s placed his firm at the center of so much action.
E. Eric Tokat
Co-President, Investment Banking
Centerview Partners
CenterView Partners Eric Tokat feels dealmaking will improve in 2024, given the recent flurry of dealmaking at end of last year and right before main JPM Healthcare Conference. He says Centerview wants to help the biotechs they invest in on their strategic path. This may translate into buyers more actively involved (more than startups want) and buyers now are in the drivers seat as far as the timeline of deals and development.
Is the megamerger dead for this year? He says it is very hard to see two major mergers happening but there will be many smaller and mid size biotech deals happening, but these deals will be more speculative in nature.. The focus for large pharma is top line growth. Most of the buyers have an infrastructure and value is more of buying and dropping it in their business so there is now a huge emphasis on due diligence on whether synergies exist or not
12:00 PM – 12:30 PM PST
Founder, legend, leader: In conversation with Nobel laureate Carolyn Bertozzi
Carolyn Bertozzi’s discoveries around bioorthogonal chemistry won the Nobel Prize in Chemistry in 2022 and are at the heart of new therapies being tested in patients. Join us as we discuss what inspires her and where she sees the next big advances.
Carolyn Bertozzi
Prof. of Chemistry, Stanford University and Baker Family Director of Sarafan ChEM-H
Stanford University
Nicole DeFeudis
MODERATOR
Editor
Endpoints News
Bioorthogonal chemistry: class of high yielding chemical reactions that proceed rapidly and selectively in biological environments without side reactions toward endogenous functions. This is also a type of ‘click chemistry’ in biological system where only specifically alter the biomolecule of interest.
Orthogonal: two chemicals not interacting with each other
Dr. Bertozzi noted she has started a new Antibody-Drug-Conjugate (ADC) company which involves designing with biorthogonal chemistry to make new functional molecules with varying properties
She noted hardly any biologists knew anything about glycobiology when she first started. However now she feels pharma and academia are working very well with each other
Bioorthogonal and Click Chemistry Curated by Prof. Carolyn R. Bertozzi, 2022 winner of the Nobel Prize in Chemistry
The 2022 Nobel Prize in Chemistry has been awarded jointly to ACS Central Science Editor-in-Chief, Carolyn R. Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen, and K. Barry Sharpless of Scripps Research, for the development of click chemistry and bioorthogonal chemistry.
To celebrate this remarkable achievement, 2022 Nobel Prize winner Professor Carolyn R. Bertozzi has curated this Bioorthogonal and Click Chemistry Virtual Issue, highlighting papers published across ACS journals that have built upon the foundational work in this exciting area of chemistry.
Bioorthogonal reactions are chemical reactions that neither interact with nor interfere with a biological system. The participating functional groups must be inert to biological moieties, must selectively reactive with each other under biocompatible conditions, and, for in vivo applications, must be nontoxic to cells and organisms. Additionally, it is helpful if one reactive group is small and therefore minimally perturbing of a biomolecule into which it has been introduced either chemically or biosynthetically. Examples from the past decade suggest that a promising strategy for bioorthogonal reaction development begins with an analysis of functional group and reactivity space outside those defined by nature. Issues such as stability of reactants and products (particularly in water), kinetics, and unwanted side reactivity with biofunctionalities must be addressed, ideally guided by detailed mechanistic studies. Finally, the reaction must be tested in a variety of environments, escalating from aqueous media to biomolecule solutions to cultured cells and, for the most optimized transformations, to live organisms.
9 JAN
9:40 AM – 10:10 AM PST
Biotech downturn survival school
Our panelists have seen the worst, and made it through to the other side. Join us for downturn survival school as our panelists talk about what sets apart the ones who make it through tough times.
These panalists think it will be specialist capital year to shine while the general capital is still sitting on the sidelines
JJ Kang
CEO
Appia Bio
“2023 was a tough year while 2020 was a boon year to start a company. We will continue to see these cycles; many of these new CEOs have never seen a biotech downturn yet and may not know how to preserve capital for the downturn”.
“Doing a partnership with Kite Pharmaceuticals early in our startp allowed us to get work done without risking a lot of capital, even if it means equity and asset dilution. That makes sense. However even if you are small insist on being an equal partner.”
“There are many investors we talk to who do not want to invest in cell therapy. Too risky now”
Carl Gordon
Managing Partner
OrbiMed Advisors
There are many macroeconomic factors affecting investment and capital today which will carry on through 2024. Not raising money when you do not need money is a bad philosophy. Always bbe raising captial. This is especially true when you have to rely on hedge funds. Parnerships howeve are sometimes the only way for small biotechs to leverage their strengths.
Joshua Boger
Executive Chair
Alkeus Pharmaceuticals, Inc.
Boger: Expect volatility for 2024. This environment feels very different than past downturns.
Even in downturns there is still lots of capital; remember access to human capital is better in a downturn and is easier to access; however it has become harder to get drug approvals
The panelists agree that access to capital and funding will be as tricky in 2024 than 2023. They did
suggest that a new funding avenue, private credit, may be a source of capital. This is discussed below:
When thinking about a private alternative investment asset class, the first thing that springs to mind is private equity. But there’s one more asset class with the word private in its name that has recently gained much attention. We’re talking about private credit.
Indeed, this once little-known investment strategy is now growing rapidly in popularity, offering private investors worldwide an exciting opportunity to diversify their portfolio with, in theory, less risky investments that yield significant returns.
Private credit investments refer to investors lending money to companies who then repay the loan at a given interest rate within the predetermined period.
The private credit market has grown significantly over the past years, rising from $875 million in 2020 to $1.4 trillion at the beginning of 2023.
Please WATCH VIDEO BY GOLDMAN SACHS ON PRIVATE CREDIT
The New Molecule: How breakthrough technologies are actually changing pharma R&D
Join us for a look at how AI, machine learning and generative technologies are actually being applied inside drugmakers’ labs. We’ll explore how new technologies are being used, their implications, how they intersect with regulatory and IP issues and how this fast-changing field is likely to evolve.
Kailash Swarna
Managing Director & Global Life Sciences Clinical Development Lead
Accenture
Artificial Intelligence is making impact in a grand way on biology in three aspects:
Speeding up target validation: now we can get through 300 molecules a day
Predicition like AlphaFold is doing; molecular simulations
Document submission especially with regulatory and IND submissions
Pamela Carroll
COO
Isomorphic Labs formerly of AlphaFold
We were first with Novartis at last year JPM and was one year old but parnering with them in that initial year was very important for sealing the deal.
They are looking now at neurologic diseases like ALS. She wondered whether ALS is actually multiple diseases and we need to stratify patients like we do in oncology trials. Their main competion is the whole tech world like Amazon, Google and other Machine Learning companies so being a tech player in the biotech world means you are not just competing with other biotechs but large tech companies as well.
Jorge Conde
General Partner
Andreessen Horowitz
Need is still great for drug discovery; early adopters show AI tools can be used in big pharma. There are lots of applications of AI in managing care; a lot of back office applications including patient triaging. He does not see big AI mergers with pharma companies – this will be mainly partnerships not M&A deals
Alicyn Campbell
Chief Scientific Officer
Evinova, a Healthtech Subsidiary of the AstraZeneca Group
There is a need to turn AI for real world example. For example AI tools were used in clinical trials to determine patient cohorts with pneumonitis. At Evinova they are determining how AI can hel[p show clinical benefit with respect to efficacy and safety
Joshua Boger at #JPM24 (Brian Benton Photography)
January 12, 2024 09:06 AM ESTUpdated 10:00 AM PeopleStartups
Vertex founder Joshua Boger on surviving downturns, ‘painful’ partnerships, and the importance of culture: #JPM24
While the JP Morgan Healthcare Conference was full of voices of measured optimism, rooting for the market to bounce back in 2024, one longtime biotech leader warned against setting any firm expectations.
Instead of predicting when the downturn may end, Vertex Pharmaceuticals founder Joshua Boger said he advises biotech leaders to expect — and plan for — volatility. Speaking Tuesday on an Endpoints News panel alongside OrbiMed’s Carl Gordon and Appia Bio CEO JJ Kang, Boger shared lessons learned on surviving downturns, striking pharma deals, and the importance of keeping a company’s culture based on his two decades of founding and leading Vertex as CEO from 1989 to 2009. The 72-year-old is now serving as executive chairman of Alkeus Pharmaceuticals, a startup developing a rare disease drug.
“I never experienced a straight line up,” Boger said. “Everything had its cycles, and it was how you respond to the cycle, not by predicting when the end is going to be, but just by responding to the present situation.”
At Boger’s first appearance at the JP Morgan conference in 1991, he said the conference’s theme was the end of biotech financing. Just a few months later, Regeneron successfully went public, rapidly changing the outlook for the whole field.
“We had no idea we were ever going to take public money,” he said. “When Regeneron did their IPO, we went, ‘Whoa, there’s something happening here,’ and we pivoted quickly.”
Vertex went public later that year. Throughout his 20-year tenure, Boger said no pharma company ever made an acquisition offer for Vertex, which now commands a market value of $110 billion and recently won the first FDA approval for a CRISPR gene editing therapy.
“We had an uber corporate policy to always make ourselves more expensive than anyone would stomach,” Boger said.
However, Vertex did strike a range of partnerships with Big Pharmas, which Boger described as a painful but necessary part of running a biotech startup.
“It’s impossible for a partnership not to slow you down,” he said. “You can and should try as hard as you can not to do that, but just count on it. They’ll slow you down.”
Boger said startups should insist on being equal partners in pharma deals, at least making sure they have a seat at a partner’s development meetings.
“Realize they’re going to be painful, it’s going to be horrible, and you need to do it,” Boger said.
While Vertex suffered through layoffs, stock price plunges, and trial failures, Boger credited a focus on culture as key to its long-term success.
“It’s the most important ingredient for a successful company,” he said. “Technology is acquirable. Culture is not acquirable. There are 10 companies that will fail because of culture for every one that succeeds, and the successful companies in retrospect will almost always have special cultural aspects that kept them through those downtimes.”
JPM24 opens with ADCs the hottest ticket in San Francisco
The overall deal flow in biopharma tapered off in 2023 but the big companies sure know what they want (what they really, really want), according to a new report from J.P. Morgan.
And that’s antibody-drug conjugates, which drove a fourth-quarter spike in licensing deal proceeds and provided a glimmer of hope to an industry battered by outside forces and grim financing prospects.
J.P. Morgan’s annual 2023 Biopharma Licensing and Venture Report arrived on the eve of the firm’s famous conference, which is set to welcome thousands of attendees in San Francisco today—East Coast weather permitting.
2023 was tough, but clinical biotechs still had a lot of opportunities to wheel and deal, according to J.P. Morgan. While licensing deals, venture investments, M&A and IPOs were down overall in the fourth quarter, deal values stayed fairly high thanks to a flurry of late-stage tie ups.
Follow the Fierce team’s coverage of the 2024 J.P. Morgan Healthcare Conference here.
Biopharma licensing partnerships accounted for $63 billion in total value during the fourth quarter from 108 deals. Just one deal—Merck’s ADC partnership with Daiichi Sankyo—accounted for $22 billion of that. Another huge one was another ADC bet, with Bristol Myers Squibb signing on to work with SystImmune for a total value of $8.4 billion. If you exclude the Merck deal, the total value of these partnerships is still higher than the previous quarter, which ended with $32.1 billion.
The total number of licensing deals compares to 149 in the same quarter a year earlier, 195 for Q4 2021 and 223 for Q4 2022.
As for venture investments, the year closed out with $17 billion total across 250 rounds, thanks to $3.5 billion earned through 79 rounds in the last quarter. Aiolos Bio snagged the title of largest venture round of the quarter with $245 million, which also proved to be the largest series A, too.
There was just one IPO in all of the fourth quarter—Cargo Therapeutics making the plunge for $300 million—and 13 overall for the year. It’s a far cry from the heyday of 2021 and experts are still unsure what 2024 will hold. J.P. Morgan reported $2.5 billion raised from 12 completed biopharma IPOs for the year on Nasdaq and NYSE. Nine out of the 12 companies had clinical programs when they took the leap to the public markets. As of December 13, five of the companies were trading above their IPO price.
As for M&A, December saw a rush of Big Pharmas snapping up companies around Christmas. J.P. Morgan tallied the fourth quarter at $37.6 billion and $128.8 billion across 112 total acquisitions for all of 2023.
AbbVie was the top buyer of the quarter with the two largest acquisitions thanks to the $10 billion outlay for ImmunoGen and $8.7 billion buy of Cerevel Therapeutics.
All of this adds up to 270 total deals in the fourth quarter total, which is lower than the third quarter which exceeded 300.
J.P. Morgan sees some big potential for smaller biopharmas looking for licensing partners, as Big Pharmas have been handing out larger upfront payments for the deals they really want.
Cancer was once again the most in-demand therapeutic areas, reaching a new height of $86.1 billion in 2023. Followed by $21.1 billion for neurological disorders.
For More Articles on Real Time Conference Coverage in this Open Access Scientific Journal see:
Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use
In this curation we wish to present two breaking through goals:
Goal 1:
Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer
Goal 2:
Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.
According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.
These eight subcellular pathologies can’t be measured at present time.
In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.
Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases
Glycation
Oxidative Stress
Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
Membrane instability
Inflammation in the gut [mucin layer and tight junctions]
Epigenetics/Methylation
Autophagy [AMPKbeta1 improvement in health span]
Diseases that are not Diseases: no drugs for them, only diet modification will help
Image source
Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease
These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:
Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL
In the Bioelecronics domain we are inspired by the work of the following three research sources:
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC
PENDING
THE VOICE of Stephen J. Williams, PhD
Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes
25% of US children have fatty liver
Type II diabetes can be manifested from fatty live with 151 million people worldwide affected moving up to 568 million in 7 years
A common myth is diabetes due to overweight condition driving the metabolic disease
There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
Thirty percent of ‘obese’ people just have high subcutaneous fat. the visceral fat is more problematic
there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects. Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
At any BMI some patients are insulin sensitive while some resistant
Visceral fat accumulation may be more due to chronic stress condition
Fructose can decrease liver mitochondrial function
A methionine and choline deficient diet can lead to rapid NASH development
Bacterial multidrug resistance problem solved by a broad-spectrum synthetic antibiotic
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
There is an increasing demand for new antibiotics that effectively treat patients with refractory bacteremia, do not evoke bacterial resistance, and can be readily modified to address current and anticipated patient needs. Recently scientists described a promising compound of COE (conjugated oligo electrolytes) family, COE2-2hexyl, that exhibited broad-spectrum antibacterial activity. COE2-2hexyl effectively-treated mice infected with bacteria derived from sepsis patients with refractory bacteremia, including a CRE K. pneumoniae strain resistant to nearly all clinical antibiotics tested. Notably, this lead compound did not evoke drug resistance in several pathogens tested. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to abrogate bacterial cell viability and the evolution of drug-resistance. Impeding these bacterial properties may occur through alteration of vital protein–protein or protein-lipid membrane interfaces – a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis. The diversity and ease of COE design and chemical synthesis have the potential to establish a new standard for drug design and personalized antibiotic treatment.
Recent studies have shown that small molecules can preferentially target bacterial membranes due to significant differences in lipid composition, presence of a cell wall, and the absence of cholesterol. The inner membranes of Gram-negative bacteria are generally more negatively charged at their surface because they contain more anionic lipids such as cardiolipin and phosphatidylglycerol within their outer leaflet compared to mammalian membranes. In contrast, membranes of mammalian cells are largely composed of more-neutral phospholipids, sphingomyelins, as well as cholesterol, which affords membrane rigidity and ability to withstand mechanical stresses; and may stabilize the membrane against structural damage to membrane-disrupting agents such as COEs. Consistent with these studies, COE2-2hexyl was well tolerated in mice, suggesting that COEs are not intrinsically toxic in vivo, which is often a primary concern with membrane-targeting antibiotics. The COE refinement workflow potentially accelerates lead compound optimization by more rapid screening of novel compounds for the iterative directed-design process. It also reduces the time and cost of subsequent biophysical characterization, medicinal chemistry and bioassays, ultimately facilitating the discovery of novel compounds with improved pharmacological properties.
Additionally, COEs provide an approach to gain new insights into microbial physiology, including membrane structure/function and mechanism of drug action/resistance, while also generating a suite of tools that enable the modulation of bacterial and mammalian membranes for scientific or manufacturing uses. Notably, further COE safety and efficacy studies are required to be conducted on a larger scale to ensure adequate understanding of the clinical benefits and risks to assure clinical efficacy and toxicity before COEs can be added to the therapeutic armamentarium. Despite these limitations, the ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. It enables the construction of a spectrum of compounds with the potential for development as a new versatile therapy for the emergence and rapid global spread of pathogens that are resistant to all, or nearly all, existing antimicrobial medicines.
2022 FDA Drug Approval List, 2022 Biological Approvals and Approved Cellular and Gene Therapy Products
Reporter: Aviva Lev-Ari, PhD, RN
SOURCE
Tal Bahar’s post on LinkedIn on 1/17/2023
Novel Drug Approvals for 2022
FDA’s Center for Drug Evaluation and Research (CDER)
New Molecular Entities (“NMEs”)
Some of these products have never been used in clinical practice. Below is a listing of new molecular entities and new therapeutic biological products that CDER approved in 2022. This listing does not contain vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, or other products that the Center for Biologics Evaluation and Research approved in 2022.
Others are the same as, or related to, previously approved products, and they will compete with those products in the marketplace. See Drugs@FDA for information about all of CDER’s approved drugs and biological products.
Certain drugs are classified as new molecular entities (“NMEs”) for purposes of FDA review. Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient drug or as part of a combination product. These products frequently provide important new therapies for patients. Some drugs are characterized as NMEs for administrative purposes, but nonetheless contain active moieties that are closely related to active moieties in products that FDA has previously approved. FDA’s classification of a drug as an “NME” for review purposes is distinct from FDA’s determination of whether a drug product is a “new chemical entity” or “NCE” within the meaning of the Federal Food, Drug, and Cosmetic Act.
To treat adults with HIV whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations Press Release
To decrease the incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia
The Center for Biologics Evaluation and Research (CBER) regulates products under a variety of regulatory authorities. See the Development & Approval Process page for a description of what products are approved as Biologics License Applications (BLAs), Premarket Approvals (PMAs), New Drug Applications (NDAs) or 510Ks.
Biologics License Applications and Supplements
New BLAs (except those for blood banking), and BLA supplements that are expected to significantly enhance the public health (e.g., for new/expanded indications, new routes of administration, new dosage formulations and improved safety).
Other Applications Approved or Cleared by the Center for Biologics Evaluation and Research (CBER)
Medical devices involved in the collection, processing, testing, manufacture and administration of licensed blood, blood components and cellular products.
There are five FDA-approved CAR-T treatments for blood cancers and two gene therapies to treat rare diseases now on the market in the U.S. The late-stage pipeline could produce several more cancer CAR-Ts and gene therapies to treat a range of diseases.
One of the biggest races to watch in the cell therapy space will be that between Gilead Sciences’ Yescarta and Bristol Myers Squibb’s Breyanzi, both of which are gunning to move their CAR-Ts into earlier lines of treatment in large B-cell lymphoma (LBCL). At ASH, both companies rolled out impressive data from their trials in the second-line setting, but Gilead could have the upper hand by virtue of its three-year head start in the market, analysts said. Gilead expects to hear from the FDA on a label expansion in the second-line setting in April.
Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRASG12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.
INTRODUCTION
Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary new class of drugs that use cancer cells’ own protein destruction machinery to selectively degrade essential tumor drivers (1). PROTACs are small molecules with two functional ends, wherein one end binds to the protein of interest, whereas the other binds to an E3 ubiquitin ligase (2, 3), bringing the ubiquitin ligase to the target protein, leading to its ubiquitination and subsequent degradation by the proteasome. PROTACs have enabled the development of drugs against previously “undruggable” targets and require neither catalytic activity nor high-affinity target binding to achieve target degradation (4). In addition, low doses of PROTACs can be highly effective at inducing degradation, which can reduce off-target toxicity associated with high dosing of traditional inhibitors (3). PROTACs have been developed for a variety of cancer targets, including oncogenic kinases (5), epigenetic proteins (6), and, recently, KRASG12C proteins (7). PROTACs targeting the androgen receptor or estrogen receptor are avidly being evaluated in clinical trials for prostate cancer (NCT03888612) or breast cancer (NCT04072952), respectively.
However, PROTACs may not escape the overwhelming challenge of drug resistance that befalls so many cancer therapies (8). Resistance to PROTACs in cultured cells has been shown to involve genomic alterations in their E3 ligase targets, such as decreased expression of Cereblon (CRBN), Von Hippel Lindau (VHL), or Cullin2 (CUL2) (9–11). Up-regulation of the drug efflux pump encoded by ABCB1—MDR1 (multidrug resistance 1), a member of the superfamily of adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporters—has been shown to convey drug resistance to many anticancer drugs, including chemotherapy agents, kinase inhibitors, and other targeted agents (12). Recently, PROTACs were shown to be substrates for MDR1 (10, 13), suggesting that drug efflux represents a potential limitation for degrader therapies. Here, using degraders (PROTACs) against bromodomain and extraterminal (BET) bromodomain (BBD) proteins and cyclin-dependent kinase 9 (CDK9) as a proof of concept, we applied proteomics to define acquired resistance mechanisms to PROTAC therapies in cancer cells after chronic exposure. Our study reveals a role for the drug efflux pump MDR1 in both acquired and intrinsic resistance to protein degraders in cancer cells and supports combination therapies involving PROTACs and MDR1 inhibitors to achieve durable protein degradation and therapeutic responses.
Fig. 1. Proteomic characterization of degrader-resistant cancer cell lines. (A) Workflow for identifying protein targets up-regulated in degrader-resistant cancer cells. Single-run proteome analysis was performed, and changes in protein levels among parent and resistant cells were determined by LFQ. m/z, mass/charge ratio. (B and C) Cell viability assessed by CellTiter-Glo in parental and dBET6- or Thal SNS 032–resistant A1847 cells treated with increasing doses of dBET6 (B) or Thal SNS 032 (C) for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. Growth inhibitory 50% (GI50) values were determined using Prism software. (D to G) Immunoblotting for degrader targets and downstream signaling in parental A1847 cells and their derivative dBET6-R or Thal-R cells treated with increasing doses of dBET6 or Thal SNS 032 for 4 hours. The dBET6-R and Thal-R cells were continuously cultured in 500 nM PROTAC. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values, quantitating either (E) the dose of dBET6 that reduces BRD2, BRD3, or BRD4 or (G) the dose of Thal SNS 032 that reduces CDK9 protein levels 50% of the DMSO control treatment, were determined with Prism software. Pol II, polymerase II. (H to K) Volcano plot of proteins with increased or reduced abundance in dBET6-R (H) or Thal-R (I) A1847 cells relative to parental cells. Differences in protein log2 LFQ intensities among degrader-resistant and parental cells were determined by paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software. The top 10 up-regulated proteins in each are shown in (J) and (K), respectively. FC, fold change. (L and M) ABCB1 log2 LFQ values in dBET6-R cells from (H) and Thal-R cells from (I) compared with those in parental A1847 cells. Data are presented as means ± SD from three independent assays. By paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software, ***P ≤ 0.001. (N) Cell viability assessed by CellTiter-Glo in parental and MZ1-resistant SUM159 cells treated with increasing doses of MZ1 for 5 days. Data were analyzed as % of DMSO control, presented as means of three independent assays. GI50 values were determined using Prism software. (O and P) Immunoblotting for degrader targets and downstream signaling in parental or MZ1-R SUM159 cells treated with increasing doses of MZ1 for 24 hours. The MZ1-R cells were continuously cultured in 500 nM MZ1. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values were determined in Prism software. (Q and R) Top 10 up-regulated proteins (Q) and ABCB1 log2 LFQ values (R) in MZ1-R cells relative to parental SUM159 cells
Fig. 2. Chronic exposure to degraders induces MDR1 expression and drug efflux activity. (A) ABCB1 mRNA levels in parental and degrader-resistant cell lines as determined by qRT-PCR. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (B) Immunoblot analysis of MDR1 protein levels in parental and degrader-resistant cell lines. Blots are representative of three independent experiments. (C to E) Immunofluorescence (“IF”) microscopy of MDR1 protein levels in A1847 dBET6-R (C), SUM159 MZ1-R (D), and Thal-R A1847 cells (E) relative to parental cells. Nuclear staining by DAPI. Images are representative of three independent experiments. Scale bars, 100 μm. (F) Drug efflux activity in A1847 dBET6-R, SUM159 MZ1-R, and Thal-R A1847 cells relative to parental cells (Par.) using rhodamine 123 efflux assays. Bars are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (G) Intracellular dBET6 levels in parental or dBET-R A1847 cells transfected with a CRBN sensor and treated with increasing concentrations of dBET6. Intracellular dBET6 levels measured using the CRBN NanoBRET target engagement assay. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 by Student’s t test. (H and I) FISH analysis of representative drug-sensitive parental and drug-resistant A1847 (H) and SUM159 (I) cells using ABCB1 and control XCE 7 centromere probes. Images of interphase nuclei were captured with a Metasystems Metafer microscope workstation, and the raw images were extracted and processed to depict ABCB1 signals in magenta, centromere 7 signals in cyan, and DAPI-stained nuclei in blue. (J and K) CpG methylation status of the ABCB1 downstream promoter (coordinates: chr7.87,600,166-87,601,336) by bisulfite amplicon sequencing in parent and degrader-resistant A1847 (J) and SUM159 (K) cells. Images depict the averaged percentage of methylation for each region of the promoter, where methylation status is depicted by color as follows: red, methylated; blue, unmethylated. Schematic of the ABCB1 gene with the location of individual CpG sites is shown. Graphs are representative of three independent experiments. (L and M) Immunoblot analysis of MDR1 protein levels after short-term exposure [for hours (h) or days (d) as indicated] to BET protein degraders dBET6 or MZ1 (100 nM) in A1847 (L) and SUM159 (M) cells, respectively. Blots are representative of three independent experiments. (N to P) Immunoblot analysis of MDR1 protein levels in A1847 and SUM159 cells after long-term exposure (7 to 30 days) to BET protein degraders dBET6 (N), Thal SNS 032 (O), or MZ1 (P), each at 500 nM. Blots are representative of three independent experiments. (Q and R) Immunoblot analysis of MDR1 protein levels in degrader-resistant A1847 (Q) and SUM159 (R) cells after PROTAC removal for 2 or 7 days. Blots are representative of three independent experiments.
Fig. 3. Blockade of MDR1 activity resensitizes degrader-resistant cells to PROTACs. (A and B) Cell viability by CellTiter-Glo assay in parental and degrader-resistant A1847 (A) and SUM159 (B) cells transfected with control siRNA or siRNAs targeting ABCB1 and cultured for 120 hours. Data were analyzed as % of control, presented as means ± SD of three independent assays. ***P ≤ 0.001 by Student’s t test. (C and D) Immunoblot analysis of degrader targets after ABCB1 knockdown in parental and degrader-resistant A1847 (C) and SUM159 (D) cells. Blots are representative, and densitometric analyses using ImageJ are means ± SD of three blots, each normalized to the loading control, GAPDH. (E) Drug efflux activity, using the rhodamine 123 efflux assay, in degrader-resistant cells after MDR1 inhibition by tariquidar (0.1 μM). Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (F to H) Cell viability by CellTiter-Glo assay in parental and dBET6-R (F) or Thal-R (G) A1847 cells or MZ1-R SUM159 cells (H) treated with increasing concentrations of tariquidar. Data are % of DMSO control, presented as means ± SD of three independent assays. GI50 value determined with Prism software. (I to K) Immunoblot analysis of degrader targets after MDR1 inhibition (tariquidar, 0.1 μM for 24 hours) in parental and degrader-resistant A1847 cells (I and J) and SUM159 cells (K). Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. (L and M) A 14-day colony formation assessed by crystal violet staining of (L) A1847 cells or (M) SUM159 cells treated with degrader (0.1 μM; dBET6 or MZ1, respectively) and MDR1 inhibitor tariquidar (0.1 μM). Images are representative of three biological replicates. (N) Immunoblotting for MDR1 in SUM159 cells stably expressing FLAG-MDR1 after selection with hygromycin. (O) Long-term 14-day colony formation assay of SUM159 cells expressing FLAG-MDR1 that were treated with DMSO, MZ1 (0.1 μM), or MZ1 and tariquidar (0.1 μM) for 14 days, assessed by crystal violet staining. Representative images of three biological replicates are shown. (P and Q) RT-PCR (P) and immunoblot (Q) analysis of ABCB1 mRNA and MDR1 protein levels, respectively, in parental or MZ1-R HCT116, OVCAR3, and MOLT4 cells.
Fig. 4. Overexpression of MDR1 conveys intrinsic resistance to degrader therapies in cancer cells. (A) Frequency of ABCB1 mRNA overexpression in a panel of cancer cell lines, obtained from cBioPortal for Cancer Genomics using Z-score values of >1.2 for ABCB1 mRNA levels (30). (B) Immunoblot for MDR1 protein levels in a panel of 10 cancer cell lines. Blots are representative of three independent experiments. (C) Cell viability by CellTiter-Glo assay in cancer cell lines expressing high or low MDR1 protein levels and treated with Thal SNS 032 for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (D to F) Immunoblot analysis of CDK9 in MDR1-low (D) or MDR1-high (E) cell lines after Thal SNS 032 treatment for 4 hours. Blots are representative, and densitometric analyses using ImageJ are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (G and H) Immunoblotting of control and MDR1-knockdown DLD-1 cells treated for 4 hours with increasing concentrations of Thal SNS 032 [indicated in (H)]. Blots are representative, and densitometric analysis data are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (I) Drug efflux activity using rhodamine 123 efflux assays in DLD-1 cells treated with DMSO or 0.1 μM tariquidar. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (J) Intracellular Thal SNS 032 levels, using the CRBN NanoBRET target engagement assay, in MDR1-overexpressing DLD-1 cells treated with DMSO or 0.1 μM tariquidar and increasing doses of Thal SNS 032. Data are % of DMSO control, presented as means ± SD of three independent assays. **P ≤ 0.01 and ***P ≤ 0.001 by Student’s t test. (K to N) Immunoblotting in DLD-1 cells treated with increasing doses of Thal SNS 032 (K and L) or dBET6 (M and N) alone or with tariquidar (0.1 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of Thal SNS 032 for CDK9 reduction (L) or of dBET6 for BRD4 reduction (N) determined with Prism. (O to T) Bliss synergy scores based on cell viability by CellTiter-Glo assay, colony formation, and immunoblotting in DLD-1 cells treated with the indicated doses of Thal SNS 032 (O to Q) or dBET6 (R to T) alone or with tariquidar. Cells were treated for 14 days for colony formation assays and 24 hours for immunoblotting.
Fig. 5. Repurposing dual kinase/MDR1 inhibitors to overcome degrader resistance in cancer cells. (A and B) Drug efflux activity by rhodamine 123 efflux assays in degrader-resistant [dBET-R (A) or Thal-R (B)] A1847 cells after treatment with tariquidar, RAD001, or lapatinib (each 2 μM). Data are means ± SD of three independent experiments. *P ≤ 0.05 by Student’s t test. (C and D) CellTiter-Glo assay for the cell viability of parental, dBET6-R, or Thal-R A1847 cells treated with increasing concentrations of RAD001 (C) or lapatinib (D). Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (E to I) Immunoblot analysis of degrader targets in parental (E), dBET6-R (F and G), and Thal-R (H and I) A1847 cells treated with increasing concentrations of RAD001 or lapatinib for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of dBET6 for BRD4 reduction (G) or of Thal SNS 032 for CDK9 reduction (I) determined with Prism. (J) Immunoblotting for cleaved PARP in dBET6-R or Thal-R A1847 cells treated with RAD001, lapatinib, or tariquidar (each 2 μM) for 24 hours. Blots are representative of three independent blots. (K to N) Immunoblotting for BRD4 in DLD-1 cells treated with increasing doses of dBET6 alone or in combination with either RAD001 or lapatinib [each 2 μM (K and L)] or KU-0063794 or afatinib [each 2 μM (M and N)] for 4 hours. Blots are representative of three independent experiments and, in (L), are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for BRD4 reduction (L) determined in Prism. (O) Colony formation by DLD-1 cells treated with DMSO, dBET6 (0.1 μM), lapatinib (2 μM), afatinib (2 μM), RAD001 (2 μM), KU-0063794 (2 μM), or the combination of inhibitor and dBET6 for 14 days. Images representative of three independent assays. (P and Q) Immunoblotting for CDK9 in DLD-1 cells treated with increasing doses of Thal SNS 032 and/or RAD001 (2 μM) or lapatinib (2 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for CDK9 reduction determined with Prism (Q). (R) Colony formation in DLD-1 cells treated with DMSO, Thal SNS 032 (0.5 μM), lapatinib (2 μM), and/or RAD001 (2 μM) as indicated for 14 days.
Fig. 6. Combining MEK1/2 degraders with lapatinib synergistically kills MDR1-overexpressing KRAS-mutant CRC cells and tumors. (A and B) ABCB1 expression in KRAS-mutant CRC cell lines from cBioPortal (30) (A) and MDR1 abundance in select KRAS-mutant CRC cell lines (B). (C) Cell viability assessed by CellTiter-Glo in CRC cells treated with increasing doses of MS432 for 5 days, analyzed as % of DMSO control. GI50 value determined with Prism software. (D) Colony formation by CRC cells 14 days after treatment with 1 μM MS432. (E) MEK1/2 protein levels assessed by immunoblot in CRC lines SKCO1 (low MDR1) or LS513 (high MDR1) treated with increasing doses of MS432 for 4 hours. (F) Rhodamine 123 efflux in LS513 cells treated with DMSO, 2 μM tariquidar, or 2 μM lapatinib. (G and H) Immunoblotting analysis in LS513 cells treated with increasing doses of MS432 alone or in combination with tariquidar (0.1 μM) or lapatinib (5 μM) for 24 hours. DC50 value for MEK1 levels determined with Prism. (I) Immunoblotting in LS513 cells treated with DMSO, PD0325901 (0.01 μM), lapatinib (5 μM), or the combination for 48 hours. (J and K) Immunoblotting in LS513 cells treated either with DMSO, MS432 (1 μM), tariquidar (0.1 μM) (J), or lapatinib (5 μM) (K), alone or in combination. (L) Bliss synergy scores determined from cell viability assays (CellTiter-Glo) in LS513 cells treated with increasing concentrations of MS432, lapatinib, or the combination. (M and N) Colony formation by LS513 cells (M) and others (N) treated with DMSO, lapatinib (2 μM), MS432 (1 μM), or the combination for 14 days. (O and P) Immunoblotting in LS513 cells treated with increasing doses of MS934 alone (O) or combined with lapatinib (5 μM) (P) for 24 hours. (Q and R) Tumor volume of LS513 xenografts (Q) and the body weights of the tumor-bearing nude mice (R) treated with vehicle, MS934 (50 mg/kg), lapatinib (100 mg/kg), or the combination. n = 5 mice per treatment group. In (A) to (R), blots and images are representative of three independent experiments, and quantified data are means ± SD [SEM in (Q) and (R)] of three independent experiments; ***P ≤ 0.001 by Student’s t test.
Fig. 7. Lapatinib treatment improves KRASG12C degrader therapies in MDR1-overexpressing CRC cell lines. (A and B) Colony formation by SW1463 (A) or SW837 (B) cells treated with DMSO, LC-2 (1 μM), or MRTX849 (1 μM) for 14 days. Images representative of three independent assays. (C to E) Immunoblotting in SW1463 cells (C and D) and SW837 cells (E) treated with DMSO, LC-2 (1 μM), tariquidar (0.1 μM) (C), or lapatinib (5 μM) (D and E) alone or in combination for 48 hours. Blots are representative of three independent experiments. (F and G) Bliss synergy scores based on CellTiter-Glo assay for the cell viability of SW1463 (F) or SW837 (G) cells treated with increasing concentrations of LC-2, lapatinib, or the combination. Data are means of three experiments ± SD. (H and I) Colony formation of SW1463 (H) or SW837 (I) cells treated as indicated (−, DMSO; LC-2, 1 μM; lapatinib, 2 μM; tariquidar, 0.1 μM) for 14 days. Images representative of three independent assays. (J) Rationale for combining lapatinib with MEK1/2 or KRASG12C degraders in MDR1-overexpressing CRC cell lines. Simultaneous blockade of MDR1 and ErbB receptor signaling overcomes degrader resistance and ErbB receptor kinome reprogramming, resulting in sustained inhibition of KRAS effector signaling.
AI enabled Drug Discovery and Development: The Challenges and the Promise
Reporter:Aviva Lev-Ari, PhD, RN
Early Development
Caroline Kovac (the first IBM GM of Life Sciences) is the one who started in silico development of drugs in 2000 using a big db of substances and computer power. She transformed an idea into $2b business. Most of the money was from big pharma. She was asking what is are the new drugs they are planning to develop and provided the four most probable combinations of substances, based on in Silicon work.
Carol Kovac
General Manager, Healthcare and Life Sciences, IBM
from speaker at conference on 2005
Carol Kovac is General Manager of IBM Healthcare and Life Sciences responsible for the strategic direction of IBM′s global healthcare and life sciences business. Kovac leads her team in developing the latest information technology solutions and services, establishing partnerships and overseeing IBM investment within the healthcare, pharmaceutical and life sciences markets. Starting with only two employees as an emerging business unit in the year 2000, Kovac has successfully grown the life sciences business unit into a multi-billion dollar business and one of IBM′s most successful ventures to date with more than 1500 employees worldwide. Kovac′s prior positions include general manager of IBM Life Sciences, vice president of Technical Strategy and Division Operations, and vice president of Services and Solutions. In the latter role, she was instrumental in launching the Computational Biology Center at IBM Research. Kovac sits on the Board of Directors of Research!America and Africa Harvest. She was inducted into the Women in Technology International Hall of Fame in 2002, and in 2004, Fortune magazine named her one of the 50 most powerful women in business. Kovac earned her Ph.D. in chemistry at the University of Southern California.
The use of artificial intelligence in drug discovery, when coupled with new genetic insights and the increase of patient medical data of the last decade, has the potential to bring novel medicines to patients more efficiently and more predictably.
Jack Fuchs, MBA ’91, an adjunct lecturer who teaches “Principled Entrepreneurial Decisions” at Stanford School of Engineering, moderated and explored how clearly articulated principles can guide the direction of technological advancements like AI-enabled drug discovery.
Kim Branson, Global head of AI and machine learning at GSK.
Russ Altman, the Kenneth Fong Professor of Bioengineering, of genetics, of medicine (general medical discipline), of biomedical data science and, by courtesy, of computer science.
Synthetic Biology Software applied to development of Galectins Inhibitors at LPBI Group
Using Structural Computation Models to Predict Productive PROTAC Ternary Complexes
Ternary complex formation is necessary but not sufficient for target protein degradation. In this research, Bai et al. have addressed questions to better understand the rate-limiting steps between ternary complex formation and target protein degradation. They have developed a structure-based computer model approach to predict the efficiency and sites of target protein ubiquitination by CRNB-binding PROTACs. Such models will allow a more complete understanding of PROTAC-directed degradation and allow crafting of increasingly effective and specific PROTACs for therapeutic applications.
Another major feature of this research is that it a result of collaboration between research groups at Amgen, Inc. and Promega Corporation. In the past commercial research laboratories have shied away from collaboration, but the last several years have found researchers more open to collaborative work. This increased collaboration allows scientists to bring their different expertise to a problem or question and speed up discovery. According to Dr. Kristin Riching, Senior Research Scientist at Promega Corporation, “Targeted protein degraders have broken many of the rules that have guided traditional drug development, but it is exciting to see how the collective learnings we gain from their study can aid the advancement of this new class of molecules to the clinic as effective therapeutics.”
2012pharmaceutical
sjwilliamspa
A pioneer in computational chemistry and organosilicon compounds, Prof. Apeloig made groundbreaking scientific contributions while mentoring generations of researchers and helping position the Technion as a global leader in science and technology.
During his presidency, he expanded interdisciplinary research, strengthened international partnerships, increased investment in research infrastructure and scholarships, and advanced collaboration between engineering, medicine, and the humanities.“Prof. Apeloig led the Technion with quiet confidence and steadfast leadership,” said Technion President Prof. Uri Sivan. “His years in office were marked by exceptional academic development and a profound impact on the State of Israel and beyond.”
The Technion was his home and family. He will be deeply missed. May his memory be a blessing.