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.

TNG348 is a synthetic lethal inhibitor of USP1 by Tango Therapeutics. Inhibiting USP1 disrupts DNA repair and replication mechanisms leading to the selective death of BRCA1/2-mutant cancer cells. Despite the clinical benefit of PARPi in treating BRCA-mutated or HRD+ tumors, some patients exhibit an inadequate response or develop resistance. USP1 inhibitors may hold promise in meeting this unmet clinical demand. This case study highlights USP1 as a synthetic lethal target, the current competitive landscape, how the Tango team overcame high microsomal clearance and hERG liabilities, and more.

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.

Nurix Therapeutics’ NX-1607 is the first oral small molecule inhibitor of CBL-B to enter clinical trials. CBL-B negatively regulates immune activation in T, B, and NK cells; while immune checkpoint inhibitors are often effective, they have limitations, including lack of efficacy in certain cancers, patient variability, and resistance. NX-1607 enhances T cell activation by gluing CBL-B in an inactive conformation and, driven by preclincial data, NX-1607 is currently in a Ph. I trial. This article details its discovery story and initial clincial results, presented at the ACS Spring 2024 meeting.

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.