BMS-986365 is a potential best-in-class heterobifunctional ligand-directed degrader of WT AR. This full case study details how this heterobifunctional degrader was engineered to have low intrinsic agonism and exert direct antagonism of WT AR through occupancy of its ligand-binding domain, how the dual modality of BMS-986365 results in deep AR pathway inhibition and allows antagonism to reinforce degradation to combat compensatory resistance mechanisms, its attractive preclinical profile, interim clinical data, how it differentiates from Arvinas’ first-to-clinic AR degraders, and more!

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.

Vactosertib is an orally bioavailable TGFβ type I receptor kinase inhibitor, that has demonstrated safety, tolerability, and clinical efficacy in combination with pomalidomide in a Ph. Ib trial for RRMM.

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor from Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.

Nested Therapeutics’ lead asset, NST-628, is an oral, brain-penetrant pan-RAF–MEK non-degrading molecular glue that lacks paradoxical pathway activation. Read the full article to learn about NST-628’s fascinating mechanism of action preventing paradoxical pathway activation, how it differentiates from other RAS/RAF/MAPK pathway inhibitors, the likely molecular origin, preclinical profile supporting clinical development, why this might be an ideal combination partner, and why this molecule is a big deal.