ISM6210: A Selective CDK4 Inhibitor for HR+/HER2- Breast Cancer Treatment

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. Citation Format: Yilin Yang, Zhongying Cao, Zhisen Zhang, Fanye Meng, Jinxin Liu, Jiamin Zheng, Zuoxiao Shi, Ling Wang, David Gennert, Suguna Rachakonda, Xiao Ding, Xin Cai, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM6210, a potent and selective CDK4 inhibitor for the treatment of HR+/HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4562.