Abstract LB223: Discovery of INV-6452, a CDK2/4 inhibitor for the treatment of HR-positive HER2-negative breast cancer resistant to current CDK4/6 therapy

Abstract CDK4/6 Inhibitors represented by palbociclib, ribociclib, abemaciclib and dalpiciclib, working through their inhibitory activities toward G1/S transition cyclin-dependent protein kinases 4 and 6 coupled with cyclins D1 and D3, have emerged as one of the mainstream therapies for HR positive HER2 negative breast cancer. However, some patients do not respond to CDK4/6 inhibitors well, and more importantly majority of patients eventually develop resistance to CDK4/6 inhibitors. Such resistance is often attributed to alterations in downstream signaling cascade, including activation of CDK2/Cyclin E activities, which can also phosphorylate retinoblastoma protein. Furthermore, cyclin E amplification/overexpression is associated with multipletumor types, with high prevalence in ovarian and endometrial cancers. Toward the goal of addressing these unmet medical needs, we have discovered and profiled INV-6452, a CDK2/4 inhibitor, and INV-2821, a highly selective CDK2 inhibitor. Both compounds showed good selectivity to CDK9, GSK3b, and CDK1. INV-6452 was highly effective in breast cancer cells that developed resistance to palbociclib in cell culture systems, while highly selective CDK4 or CDK2 inhibitors alone had limited effect. INV-6452 showed tumor inhibitory activities in multiple xenograft models including breast cancer and other tumor types. Additionally, INV-6452 had a limited impact on the proliferation and myeloid-specific differentiation of human hematopoietic stem and progenitor cells. The promising profiles of INV-6452 suggest its potential in addressing unmet medical needs, and its clinical development is being planned. Citation Format: Chang Bai, Nansong Xia, Yexing Cao, Shujuan Huang, Danqi Chen, Hongjian Yang, Lishan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun. Discovery of INV-6452, a CDK2/4 inhibitor for the treatment of HR-positive HER2-negative breast cancer resistant to current CDK4/6 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB223.