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.

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.

Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.

GDC-1971 is an orally bioavailable allosteric inhibitor of the SHP2 phosphatase discovered by Relay Therapeutics, and in clinical development by Genentech both as a monotherapy and in combination with several anticancer therapies. SHP2 inhibitors are being hotly pursued since they may combine with numerous classes of clinically important agents. This article provides a primer on SHP2 as an oncology target, the disclosed molecules in the space, how RLY-1971 was identified, and what the industry is watching for.

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.