KEAP1 inhibition/NRF2 activation has been hotly pursued in recent years for immunology indications; however, in oncology, NRF2 degradation has been posited as a novel therapeutic mechanism for specific cancers. Vividion has already disclosed work on covalent KEAP1 inhibitors, but at the recent ACS Fall 2024 meeting, the structure and discovery story of their clinical oral covalent activator of KEAP1 were disclosed, identified through careful analysis of the data from their inhibitor screen.

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.

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.

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.

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.