LIVE 9/21 12:50 pm Plenary Keynote Program at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston
http://www.discoveryontarget.com/
http://www.discoveryontarget.com/crispr-therapies/
#BostonDOT16
@BostonDOT
Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a
Media Partner of CHI for CHI’s 14th AnnualDiscovery on Target taking place September 19 – 22, 2016 in Boston.
In Attendance, streaming LIVE using Social Media
Aviva Lev-Ari, PhD, RN
Editor-in-Chief
http://pharmaceuticalintelligence.com
Wednesday, September 21
12:50 pm Plenary Keynote Program
Wednesday, September 21, 2016 | 12:55 – 2:40 pm
12:55 Event Chairperson’s Opening Remarks
Cindy Crowninshield, RDN, LDN, Conference Director, Cambridge Healthtech Institute
Sponsored by
1:00 Plenary Keynote Introduction – Enabling Epigenetic Drug Discovery through Quality Proteins and Assay Services
Ekaterina Kuznetsova, Ph.D., Research Scientist, Reaction Biology Corporation
Epigenetic proteins have recently gained traction as a class of drug targets in both academia and industry. RBC is continuously expanding its epigenetic product and service line with a focus on providing (1) validated epigenetic biochemical assays, (2) epigenetic cell-based assays and (3) characterized epigenetic proteins to the drug discovery community.
- Epigenetics Drug Discovery – Reagents
- Recombinant protein products
- Bromodomains -family-wide coverage, BromoMELT -selectivity profiling – compound Profile
- HMT substrate – histone tail peptidesnative nucleosomes
- HIT – Assay Serives: in vitro Screening –
- SBIR Funded Bromodomain Chimical probe Discovery projects
- In-house libraries: BRD4-1 Screening statistics: Selectivity profiling of HIT
- Radioisotope
- Fluorescence, HTRF
- Binding Interactions” Protein: Peptide; Protein: Compound
- Custom assays – New tatgets, MOA studies
- Profiilng: specificity
- Assays and Proteins
1:15 Open Innovation Partnerships to Bridge the Gap from GWAS to Drug Targets
Jeffrey Barrett, D.Phil., Founding Director, OpenTargets.org; Group Leader, Wellcome Trust Sanger Institute
Public-Private Association: Publish all results for Global access
- Biogen/GSK
- European Bioinformatics Institute (EBI),
- Wellcome Trust Sanger Institute – Cellular, Infection, Cancer & Aging, Human genetics
- GWAS for complex diseases
- IBD – 200 genetic variations and risks for IBD – what genes
- Oncology, Immunology, Neurodegeneration: Enabling resources, Genetics as tools Human cellualr experiments
Aaron Day-Williams, Ph.D., Biogen Scientific Lead, Open Targets; Associate Director and Head, Statistical Genetics, Biogen
Nearly 85% of candidate drugs that enter clinical trials fail, and many of these are found not to work only after progression to expensive late phase trials. Fewer new medicines are coming to market, and those that do are more expensive because their success must pay for themselves as well as the development costs of the failures. It is therefore essential to find analyses and experiments that can test whether modulating a particular target will achieve therapeutic benefit in a particular disease. The field of complex disease genetics has been transformed in the last ten years by genome-wide association studies, low cost genome sequencing and rapid advances in our understanding of cellular phenotypes. We will describe how human genetics and large-scale genomics can change how we approach therapeutic target validation, and how open innovation partnerships involving pharma industry scientists working closely with academics can best bring these cutting edge datasets to bear on the problem. For example, TargetValidation.org, which is open to users worldwide, in industry or academia, integrates a dozen databases for prioritizing targets in a single analysis framework enabled by new statistical techniques and disease ontologies. We will also describe our improved analysis pipeline to connect GWAS hits to causal genes.
- Alzheimer’s Disease (AD) –>>> antibody aducanumab reducd ABCA7 –
- Propagation of Inference
- Ontology is a graph connecting information with evidence
- AD GWAS – convert GWAS Locus to Therapeutical/Hypothesis Proposed MOA Target
- Biomarker association with disease
- SNPs
- Causal Variants/Causal Gene Identification: Aggregate SKAT – Posterior Probability: Neuronal integrity, Amyloid plaques, Neural brilliant
2:00 Cell-Penetrating Mini-Proteins
Gregory L. Verdine, Ph.D., Erving Professor, Chemistry, Departments of Stem Cell and Regenerative Biology, Chemistry and Chemical Biology, and Molecular and Cellular Biology, Harvard University and Harvard Medical School
It has been estimated that as few as 10-15% of all potential targets are targetable in vivo by either biological or small molecules. To address this deficiency, we and FOG Pharmaceuticals are developing cell-penetrating mini-proteins, molecules that combine the ability of proteins to target large flat surfaces, with the ability of small molecules to penetrate cells. Progress on the development of cell-penetrating mini-proteins will be reviewed in this talk.
- Cell-Penetrating Miniproteins – Biologics vs small molecules
- 10% – Biologics – limited to targets outside the cell
- 10% – Small molecules – limited targets with hydrophobic pockets – contact surface areas
- Undrugable targets >80% and Drugable 20%
- 80%-90% of human proteins cannot be targeted by established modalities
- Biotech $250Bil and
- Big Pharma $750Bil
- Emerging of TARGETING SCIENCE – FILING the GAP enabling advancement:
- Gene Therapy
- pharmacogenomics
- CRISPR-directed
- Adeno Viruses – anti vescicule trafficing
- ADC
- antisense
- Intracellular
- Cell-Penetrating Mini-Proteins combine the synthetic
- Stripping DOwn a Protein to its Business End: Interaction domain come to contact with bioactive: ligand and interaction unfolding – low binding affinity
- The all-hydrocarbon alpha helix stapling system – enhancement of alpha-helicity, proteolytic stability, serum half life
- Cellular uptake of a stapled peptide: FITC-labled Peptide, FITC-Labeled SAHBa,
- SAHB Suppresses Leukemia In Vivo: Vehicle vs SAHBs(g-E) – Tumor burden
- A dual antagonist of hDM2 and hDMx/4 [negative regulator: 253 tumor]
- alpha helic peptide drug development: for p53
- SAHM1 bridges the ICL/CSL interface: ICN and CSL and dnMAML
Gary Gilliland
Melanie Comejo
Andrew Kung
- Discovery of direct-acting beta-catenin antagonists: Staple peptide –
- Transcription factors: DIscovery of direct-acting beta-catenin antagonists
- multiple staple configurations ->> lead optimization
- Amino-staple Target: Cell penetration by second-generation
- If no known helical interactor? Raf and K-Ras
- Sub-nM antagonists, effector domain binder,
- Screening system = yeast Surface Display app – strip staple Yeast Surface expression and add Staple
- Ras-peptide interaction in vivo
- Ras double the peptide Complex at 2.15 A
Cell-penetrating all Ras isophorme
- selection mutation inhibitors – Amide ptoton management in cyclosporine A – Hydrogen bonded –
- Amide proton management in Pro-lock system
- Pro-lock systme: N3
- 3rd – Generation systems with Pfizer
- Challenges:
- extensive screening campaign
- Endocytic uptake and release apthways
- blood is not reliable indicator of vs tissue concentration of drug
Fogpharma.com
Speaker Biographies:
Jeffrey Barrett, D.Phil., Founding Director, Open Targets; Group Leader, Wellcome Trust Sanger Institute
Jeffrey Barrett has been involved in Open Targets since its inception in 2014 and began his role as Head on 1 May 2015. Jeff is a statistical geneticist who has led several of the largest genome-wide association studies of complex disease. He first became interested in human genetics in Mark Daly’s lab at the Whitehead Institute before moving to Lon Cardon’s group in Oxford, where he received a D.Phil. in statistical genetics. Jeff was an analyst in the Wellcome Trust Case Control Consortium, and led early GWAS meta-analyses in inflammatory bowel disease and type 1 diabetes while a postdoc with David Clayton in Cambridge. Since joining the Sanger Institute as a group leader in 2008, he has used next-generation sequencing in thousands of individuals to find variation associated with both rare and common human diseases.
Aaron Day-Williams, Ph.D., Biogen Scientific Lead, Open Targets; Associate Director and Head, Statistical Genetics, Biogen
Aaron Day-Williams is a statistical geneticist and bioinformatician interested in utilizing human genetics to elucidate new targets, identify biomarkers and stratify patients. He joined Biogen in May 2012. Before joining Biogen he was a postdoctoral fellow at the Wellcome Trust Sanger Institute in Hinxton, UK, where he studied the genetics of osteoarthritis, type II diabetes and body mass index using 1000 genomes imputation-based GWAS, whole-exome sequencing and whole-genome sequencing. In addition to the gene-mapping projects, he was involved in developing methods for the analysis of rare variants. Aaron’s graduate work was performed in the labs of Dr. Eric Sobel and Dr. Kenneth Lange at UCLA, where he developed a set of methods to estimate kinship coefficients for use in gene mapping methods from GWAS chip genotyping without prior information on relationships.
Gregory L. Verdine, Ph.D., Erving Professor, Chemistry, Departments of Stem Cell and Regenerative Biology, Chemistry and Chemical Biology, and Molecular and Cellular Biology, Harvard University and Harvard Medical School
Gregory Verdine is a pioneer in the field of chemical biology, a serial biotech entrepreneur and a life science venture capitalist. In an independent academic career at Harvard University and Harvard Medical School spanning nearly three decades, he has elucidated the molecular mechanism of epigenetic DNA methylation and the pathways by which certain genotoxic forms of DNA damage are surveilled in and eradicated from the genome. He is a leading figure in the field of new therapeutic modalities, and has developed a new class of therapeutics termed stapled peptides, which are currently in clinical development and have received much attention for their ability to drug targets previously considered “undruggable”. Dr. Verdine has made important contributions in the translation of bench science to the bedside. He has founded or co-founded a number of successful biotechnology companies, including Enanta Pharmaceuticals (Nasdaq ENTA), Gloucester Pharmaceuticals (acquired by Celgene), Tokai Pharmaceuticals (Nasdaq TKAI), WaVe Life Sciences (Nasdaq WVE), Eleven Biotherapeutics (Nasdaq EBIO), Warp Drive Bio, Aileron Therapeutics, and FogPharma. To date, these companies have succeeded in gaining FDA approval for two drugs, romidepsin (Gloucester/Celgene) and paritaprevir (Enanta/AbbVie). He has also worked in the venture capital industry as a Venture Partner with Apple Tree Partners, Third Rock Ventures, and WuXi Healthcare Ventures, and as a Special Advisor to Texas Pacific Group. He co-founded and served as the founding President of the non-profit Gloucester Marine Genomics Institute and Gloucester Biotechnology Academy, for which he continues to serve as Director. Dr. Verdine is Chairman of the Board of Directors of WaVe Life Sciences, and is a Director of Warp Drive Bio, for which he also Chairs the company’s Scientific Advisory Board. He is currently President and CEO of FogPharma, a biotechnology company focused on a transformative drug discovery platform based on Cell-Penetrating Mini-Proteins. Dr. Verdine serves on the Board of Scientific Consultants of the Memorial Sloan Kettering Research Institute and on the Board of Scientific Advisors of the National Cancer Institute. Dr. Verdine holds a Ph.D. in chemistry from Columbia University, a BS in chemistry from St. Joseph’s University, and served as an NIH postdoctoral fellow in molecular biology at MIT and Harvard Medical School. He has won numerous prestigious awards, including most recently the AACR Award for Excellence in Chemistry in Cancer Research, and the Nobel Laureate Signature Award.
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