ORIC-533, a potential best-in-class oral inhibitor of CD73 from ORIC Pharmaceuticals, is currently in a Ph. Ib trial for relapsed/refractory multiple myeloma (MM). It inhibits the CD73-mediated conversion of AMP to adenosine which generates an immunosuppressive tumor microenvironment and has the potential to be a next-generation immunotherapy. The in-depth use of X-ray structures led the team to discover a novel set of phosphonate bioisosteres which acheived bioavailability in a polar scaffold. The structure and discovery of ORIC-533 were recently disclosed at the ACS Spring 2024 Meeting.

A second-generation AR bifunctional degrader for drug-resistant prostate cancer. ARV-766 is Arvinas’ second bifunctional CRL4 CRBN E3 ligase-based androgen receptor (AR) degrader to enter the clinic for the treatment of prostate cancer (PCa), after ARV-110 (bavdegalutamide) . The glutarimide recruiting element is notable as it is simpler than [...]

TNG462, developed by Tango Therapeutics, is a potential best-in-class, oral, protein arginine methyltransferase 5 (PRMT5) inhibitor currently in Ph. I/II clinical trial for MTAP-deleted solid tumors. TNG462 is designed to cooperatively bind to PRMT5 when complexed with its endogenous inhibitor methylthioadenosine (MTA), which accumulates in MTAP-deleted tumors. This triggers synthetic lethality in cells with an MTAP-deletion and spares healthy tissues with low MTA levels. A CNS-permeable analogue, TNG908, is also entering clinical trials for MTAP-deleted glioblastoma.

RMC-9805 is a first-in-class, covalent KRAS(G12D)(ON) molecular glue inhibitor from Revolution Medicines that uses a cyclophilin A (CypA)-recruiting tricomplex mechanism combined with a finely tuned aziridine covalent handle to inhibit the previously “undruggable” KRAS(G12D) mutant. Read our coverage of the discovery story, disclosed at the AACR 2024 meeting in San Diego, to discover how structural and modeling insights were key to engaging a poorly nucleophilic mutant Asp, how RMC-9805 synergizes with PD-1 inhibitors, and the progress this remarkable compound is making in the clinic.

RMC-6236 is a non-covalent pan-RAS(ON) inhibitor from Revolution Medicines, which shows remarkable efficacy in tumors driven by RAS mutants that were previously considered “undruggable,” such as G12V/D/A/S, G13X, and Q61X. RMC-6236 exerts its action via a “tri-complex” mechanism, gluing RAS to the ubiquitously expressed chaperone protein, cyclophilin A. Our in-depth article covers the presentation given at the AACR 2024 meeting, which outlines the discovery and preclinical profile of RMC-6236 as well as the latest clinical updates.