ISM6210, a potent and selective CDK4 inhibitor for the treatment of HR+/HER2- breast cancer

CDK4/6 kinases drive the G1-S cell cycle transition, and overactive cyclin-CDK4/6 complexes are common across cancer types. While clinically approved CDK4/6 inhibitors have benefited patients with HR+/HER2- breast cancer, their efficacy is constrained by dose-limiting hematological toxicities, particularly CDK6-driven myelosuppression. Hematopoietic stem cell activation relies primarily on CDK6, but breast cancer cells are more dependent on CDK4, suggesting a potential therapeutic window for a CDK4-selective inhibitor. Here, we report the development and preclinical characterization of ISM6210, an orally bioavailable CDK4 inhibitor with high selectivity over CDK6. ISM6210 demonstrated potent inhibition of the CDK4/Cyclin D1 complex in enzymatic assays with nanomolar IC50 values and good selectivity over CDK6 and other CDKs. Kinome profiling revealed minimal off-target activity, confirming its high selectivity. In cellular assays, ISM6210 selectively targeted CDK4-dependent breast cancer cells over CDK6-dependent cells. Notably, in human hematopoietic stem cell assays, ISM6210 exhibited an IC50 value about 30-fold higher than the dual CDK4/6 inhibitor Palbociclib against human hematopoietic stem cells, suggesting reduced myelosuppressive potential. Mechanistically, ISM6210 effectively blocked Rb phosphorylation and the G1/S cell cycle transition, resulting in growth arrest in HR+ breast cancer cell lines. In vivo , ISM6210 achieved robust anti-tumor activity at 30 mg/kg BID across multiple HR+ breast cancer xenograft models with notable tumor enrichment. In addition to its robust biological potency and high selectivity, ISM6210 exhibited favorable drug-like properties, including desirable in vitro ADMET profiles, excellent in vivo exposure and clearance, and good oral bioavailability across multiple preclinical species. Collectively, these findings establish ISM6210 as a potent and selective CDK4 inhibitor that delivers strong efficacy and a promising hematologic safety margin for HR+/HER2- breast cancer treatment.