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!

Kymera’s KT-413 is a CRBN-based dual-mechanism degrader that degrades both IRAK4 and the transcription factors IKZF1/3, acting as an IMiD, with promising clinical activity for the treatment of ABC-like subtype of DLBCL. This fascinating case study demonstrates how a dual-mechanism degrader of IKZF1/3 and IRAK4 can be designed to maximize NF-κB inhibition while simultaneously upregulating the Type I interferon response. This approach restores the apoptotic response and enables oncogene-mediated cell death, resulting in a robust antiproliferative and pro-apoptotic effect in MYD88 mutants.

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.

This month’s cover molecule, Pfizer’s PF-07321332 (nirmatrelvir, API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which has been submitted to the FDA by Pfizer for emergency approval for Covid treatment. Interim data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for this month’s [...]

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.