Valentina (Seung-Hwa) Kwak

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

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!