ORIC-944 is a second-generation, orally bioavailable PRC2 inhibitor, targeting the allosteric EED subunit. EZH2 inhibitors typically require frequent dosing due to poor drug-like properties. This article describes the previously undisclosed structure-based design of ORIC-944 into a potential best-in-class PRC2 inhibitor with enhanced solubility, metabolic stability, and prolonged clinical half-life compared to EZH2 inhibitors. It also highlights ORIC-944's capability to reprogram refractory, AR-independent prostate tumors to an AR-dependent state, the synthesis, clinical data, and more!

VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.

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.

Pfizer’s oral, CDK4-selective inhibitor PF-07220060 has the potential to revolutionize treatment of HR+/HER2- breast cancer through avoiding the neutropenia DLTs associated with SoC CDK4/6 drugs and permitting greater coverage of the desired CDK4 target. Our full article outlines data presented at AACR 2024, covering the molecule’s course from in silico-informed screen, through structurally enabled optimization against CDK6 and GSK-3β to promising preclinical profile. Fresh clinical data showed efficacy and tolerability supporting PF-07220060's clinical progression.

Arcus Biosciences recently disclosed the structure and discovery story of their oral HIF-2α inhibitor casdatifan (AB521) at the ACS Fall 2024 First Time Disclosures session in Denver. Read on to find out how the team overcame serum shifts and metabolism issues to deliver into the clinic what could potentially be a best-in-class compound, superior to the recently approved inhibitor, belzutifan.