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Recently, researchers at Mount Sinai were able to develop a therapeutic agent that shows high levels of effectiveness in Vitro disrupting a biological pathway that allow cancer to survive. This finding is according to a paper which was published in Cancer Discovery, which is a Journal of the American Association of cancer research in July 2021.
The therapy in which they focus on is a molecule named MS21, which causes the degradation of AKT which is an enzyme that is very active and present in cancers. In this study there was much evidence that pharmacological degradation of AKT is a feasible treatment for cancer’s which have a mutation in certain genes.
AKT is a cancer gene that encodes an enzyme that is abnormally activated in cancer cells to stimulate tumor growth. The degradation of AKT reverses all these processes which ultimately inhibits further tumor growth.
“Our study lays a solid foundation for the clinical development of an AKT degrader for the treatment of human cancers with certain gene mutations,” said Ramon Parsons, MD, Ph.D., Director of The Tisch Cancer Institute and Ward-Coleman Chair in Cancer Research and Chair of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. “Examination of 44,000 human cancers identified that 19 percent of tumors have at least one of these mutations, suggesting that a large population of cancer patients could benefit from therapy with an AKT degrader such as MS21.”
https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.
MS21 was tested and human cancer derived cell lines, is used in Laboratories as a model to study the efficacy of different cancer therapies.
At Mount Sinai they were looking to develop MS21 with an industry partner in order to open clinical trials for patients.
“Translating these findings into effective cancer therapies for patients is a high priority because the mutations and the resulting cancer-driving pathways that we lay out in this study are arguably the most commonly activated pathways in human cancer, but this effort has proven to be particularly challenging,” said Jian Jin, Ph.D., Mount Sinai Professor in Therapeutics Discovery and Director of the Mount Sinai Center for Therapeutics Discovery at Icahn Mount Sinai. “We look forward to an opportunity to develop this molecule into a therapy that is ready to be studied in clinical trials.”
https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.
Image credit: National Cancer Institute
Original article:
Researchers develop novel therapy that could be effective in many cancers
staff, S. X. (2021, July 23). R. Medical Xpress – by The Mount Sinai Hospital
https://medicalxpress.com/news/2021-07-therapy-effective-cancers.html.
UPDATE 12/12/2022
From Mt. Sinai
Advancing cancer precision medicine by creating a better toolbox for cancer therapy
Jian Jin1,2,3,4,5*, Arvin C. Dar1,2,3,4, Deborah Doroshow1
| A |
mong approximately 20,000 proteins in the human proteome, 627 have been identified by cancer-dependency studies as priority cancer targets, which are functionally important for various cancers. Of these 600-plus priority targets, 232 are enzymes and 395 are nonenzyme proteins (1). Tremendous progress has been made over the past several decades in targeting enzymes, in particular kinas-es, which have suitable binding pockets that can be occupied by small-molecule inhibitors, leading to U.S. Food and Drug Administration (FDA) approvals of many small-molecule drugs as targeted anticancer thera-
1Tisch Cancer Institute; 2Department of Oncological Sciences; 3Department of Pharmacological Sciences; 4Mount Sinai Center for Therapeutics Discovery; 5Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY
*Corresponding author: jian.jin@mssm.edu
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pies. However, most of the 395 nonenzyme protein targets, including transcription factors (TFs), do not have suitable binding pockets that can be effectively targeted by small molecules. These targets have consequently been considered undruggable; however, new cutting-edge approaches and technologies have recently been developed to target some of these “un-druggable” proteins in order to advance precision oncology.
TPD, a promising approach to precision cancer therapeutics
Targeted protein degradation (TPD) refers to the process of chemically eliminating proteins of interest (POIs) by utilizing small molecules, which are broadly divided into two types of modalities: PROteolysis Targeting Chimeras (PROTACs) and molecular glues (2). PROTACs are het-erobifunctional small molecules that contain two moieties: one binding the POI, linked to another binding an ubiquitin E3 ligase. The induced proximity between the POI and ubiquitination machinery leads to selective polyubiquitylation of the POI and its subsequent degradation by the ubiquitin–proteasome system (UPS). Molecular glues are monovalent small molecules, which, when built for TPD, directly induce interactions between the POI and an E3 ligase, also resulting in polyubiquitylation and subsequent degradation of the POI by the UPS. One of the biggest potential advantages of these therapeutic modalities over traditional inhibitors is that PROTACs and molecular glues can target undruggable proteins. Explosive growth has been seen in the TPD field over recent years (2, 3). Here, we highlight several recent advancements.
TF-PROTAC, a novel platform for targeting undruggable
tumorigenic TFs
Many undruggable TFs are tumorigenic. To target them, TF-PROTAC was developed (4), which exploits the fact that TFs bind DNA in a sequence-specific manner. TF-PROTAC was created to selectively bind a TF and E3 ligase simultaneously, by conjugating a DNA oligonucleotide specific for the TF of interest to a selective E3 ligase ligand. As stated earlier, this simultaneous binding and induced proximity leads to selective polyubiquitination of the TF and its subsequent degradation by the UPS. TF-PROTAC is a cutting-edge technology that could potentially provide a universal strategy for targeting most undruggable tumorigenic TFs.
Development of novel PROTAC degraders
WDR5, an important scaffolding protein, not an enzyme, is essential for sustaining tumorigenesis in multiple cancers, including MLL-rearranged (MLL-r) leukemia. However, small-molecule inhibitors that block the pro-tein–protein interaction (PPI) between WDR5 and its binding partners exhibit very modest cancer cell–killing effects, likely due to the confounding fact that these PPI inhibitors target only some—but not all—of WDR5’s on-cogenic functions. To address this shortcoming, a novel WDR5 PROTAC, MS67, was recently created using a powerful approach that effectively eliminates the protein and thereby all WDR5 functions via ternary complex structure-based design (Figure 1) (5). MS67 is a highly effective WDR5 degrader that potently and selectively degrades WDR5 and effectively suppresses the proliferation of tumor cells both in vitro and in vivo. This study provides strong evidence that pharmacological degradation of WDR5 as a novel therapeutic strategy is superior to WDR5 PPI inhibition for treating WDR5-dependent cancers.
EZH2 is an oncogenic methyltransferase that catalyzes histone H3 lysine 27 trimethylation, mediating gene repression. In addition to this canonical function, EZH2 has numerous noncanonical tumorigenic functions. EZH2 enzymatic inhibitors, however, are generally ineffective in
suppressing tumor growth in triple-negative breast cancer (TNBC) and MLL-r leukemia models and fail to phenocopy antitumor effects induced by EZH2 knockdown strategies. To target both canonical and noncanon-ical oncogenic functions of EZH2, several novel EZH2 degraders were recently developed, including MS1943, a hydrophobic tag–based EZH2 degrader (6), and MS177, an EZH2 PROTAC (7). MS1943 and MS177 effectively degrade EZH2 and suppress in vitro and in vivo growth in TNBC and MLL-r leukemia, respectively, suggesting that EZH2 degraders could provide a novel and effective therapeutic strategy for EZH2-dependent tumors.
MS21, a novel AKT PROTAC degrader, was developed to target activated AKT, the central node of the PI3K–AKT–mTOR signaling pathway (8). MS21 effectively suppresses the proliferation of PI3K–PTEN pathway-mutant cancers with wild-type KRAS and BRAF, which represent a large percentage of all human cancers. Another recent technology that expands the bifunctional toolbox for TPD is the demonstration that the E3 ligase KEAP1 can be leveraged for PROTAC development using a selective KEAP1 ligand (9). Overall, tremendous progress has been made in discovering novel degraders, some of which have advanced to clinical development as targeted therapies (2, 3).
Novel approaches to selective TPD in cancer cells
To minimize uncontrolled protein degradation in normal tissues, which may cause potential toxicity, a new technology was developed that incorporates a light-inducible switch, termed “opto-PROTAC” (10). This switch serves as a caging group that renders opto-PROTAC inactive in all cells in the absence of ultraviolet (UV) light. Upon UV irradiation, however, the caging group is removed, resulting in the release of the active degrader and spatiotemporal control of TPD in cancer cells. Another strategy to achieve selective TPD in cancer over normal cells is to cage degraders with a folate group (11, 12). Folate-caged degraders are inert and selectively concentrated within cancer cells, which overexpress folate receptors compared to normal cells. The caging group is subsequently removed inside tumor cells, releasing active degraders and achieving selective TPD in these cells. These novel approaches potentially enable degraders to be precision cancer medicines.
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Frontiers of Medical Research: Cancer
Trametiglue, a novel and atypical molecular glue
The RAS–RAF–MEK–ERK signaling pathway, one of the most frequently mutated pathways in cancer, has been intensively targeted. Several drugs, such as the KRAS G12C inhibitor sotorasib and the MEK inhibitor trametinib, have been approved by the FDA. A significant advancement in this area is the discovery that trametinib unexpectedly binds a pseudokinase scaffold termed “KSR” in addition to MEK through interfacial contacts (13). Based on this structural and mechanistic insight, tra-metiglue, an analog of trametinib, was created as a novel molecular glue to limit adaptive resistance to MEK inhibition by enhancing interfacial binding between MEK, KSR, and the related homolog RAF. This study provides a strong foundation for developing next-generation drugs that target the RAS pathway.
TF-DUBTAC, a novel technology to stabilize undruggable tumor-suppressive TFs
Complementary to degrading tumorigenic TFs, stabilizing tumor-suppressive TFs could provide another effective approach for treating cancer. While most tumor-suppressive TFs are undruggable, TF-DUBTAC was recently developed as a generalizable platform to stabilize tumor-suppressive TFs (14). Deubiquitinase-targeting chimeras (DUBTACs) are heterobifunctional small molecules with a deubiquitinase (DUB) ligand linked to a POI ligand, which stabilize POIs by harnessing the deubiq-uitination machinery (15). Similar to TF-PROTAC, TF-DUBTAC exploits the fact that most TFs bind specific DNA sequences. TF-DUBTAC links a DNA oligonucleotide specific to a tumor-suppressive TF with a selective DUB ligand, resulting in simultaneous binding of the TF and DUB. The induced proximity between the TF and DUB leads to selective deubiquiti-
Putting a bull’s-eye on cancer’s back
Scientists are aiming the immune systems’ “troops” directly at tumors to better treat cancer
Joshua D. Brody, Brian D. Brown
| I |
mmunotherapy has transformed the treatment of several types of cancers. In particular, immune checkpoint blockade (ICB), which reinvigorates killer T cells, has helped extend the lives of many patients with advanced-stage lung, bladder, kidney, or skin cancers. Unfortunately, ~80% of patients do not respond to current immunotherapies or even-tually relapse. Emerging data indicate that one of the most profound ways cancers resist immunotherapy is by keeping killer T cells out of the tumor and putting other immune cells in a suppressed state (1). This understanding is giving rise to a new frontier in immunotherapy that is using synthetic biology and other approaches to reprogram the tumor from immune “cold” to immune “hot,” so T cells can be recruited to the tumor, and enter, target, and destroy the cancer cells (2) (Figure 1).
Cancers protect themselves by keeping out immune cells
Cancers grow in tissues like foreign invaders. Though they start from healthy cells, mutations turn cells malignant and allow them to grow unchecked. T cells can kill malignant cells that express mutated proteins, but cancers employ strategies to fend off the T cells. One way they do this is
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nation of the TF and its stabilization. As an exciting new technology, TF-DUBTAC provides a potential general strategy to stabilize most undrugga-ble tumor-suppressive TFs for treating cancer.
Future outlook
The breathtaking pace we are seeing in the development of innovative approaches and technologies for advancing cancer therapies is only expected to accelerate. The promising clinical results achieved by PROTACs with established targets are particularly encouraging and pave the way for development of PROTACs for newer and more innovative targets. These groundbreaking discoveries have now put opportunities to fully realize cancer precision medicine within our reach.
References
- F. M. Behan et al., Nature 568, 511–516 (2019).
- B. Dale et al., Nat. Rev. Cancer 21, 638–654 (2021).
- A. Mullard, Nat. Rev. Drug Discov. 20, 247–250 (2021).
- J. Liu et al., J. Am. Chem. Soc. 143, 8902–8910 (2021).
- X. Yu et al., Sci. Transl. Med. 13, eabj1578 (2021).
- A. Ma et al., Nat. Chem. Biol. 16, 214–222 (2020).
- J. Wang et al., Nat. Cell Biol. 24, 384–399 (2022).
- J. Xu et al., Cancer Discov. 11, 3064–3089 (2021).
- J. Wei et al., J. Am. Chem. Soc. 143, 15073–15083 (2021).
- J. Liu et al., Sci. Adv. 6, eaay5154 (2020).
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N. J. Henning et al., Nat. Chem. Biol. 18, 412–421 (2022
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