Abstract ND12: Discovery of PF-07220060, a potent and selective CDK4 inhibitor

Abstract PF-07220060 was developed based on the clinical need to improve efficacy and safety outcomes in patients treated with currently approved dual CDK4/6 inhibitors, including Palbociclib. Although all dual CDK4/6 inhibitors increase response rates and prolong disease control, they show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at doses necessary to extinguish cell cycling in tumors. Human ER+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, or cells enriched for neutrophil precursors or hematopoietic stem cells. This is primarily due to the compensatory role of CDK6 in these compartments. These observations prompted us to develop PF-07220060, an aminopyrimidine-based inhibitor, endowed with 20-fold and 4-fold increased selectivity for CDK4 over CDK6 when compared to Palbociclib and Abemaciclib/Ribociclib, respectively. CDK4-over-CDK6 selectivity is explained by G-loop conformational differences between the two kinases, with the G-loop of CDK4 being more flexible, assuming a more open conformation when bound to CDK4 selective versus non-selective inhibitors. PF-07220060 reduces dose-limiting neutropenia in beagle dogs by 15-fold when compared with Palbociclib, consistent with early clinical data obtained with PF-07220060. Higher tolerated plasma concentrations of PF-07220060 versus dual CDK4/6 inhibitors enable increased inhibition of CDK4 kinase activity in tumors. This translates to improved tumor growth inhibition across CDK4-driven models of human breast and prostate cancer at clinically relevant doses. Our work establishes proof-of-concept for CDK4 selective inhibition and introduces a best-in-class CDK4 inhibitor for treatment of HR+ HER2- breast cancer and other CDK4 dependent tumor types. Citation Format: Lars Anders, Gary Gallego. Discovery of PF-07220060, a potent and selective CDK4 inhibitor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr ND12.