Abstract 5338: TY-1781, a potent and highly selective CDK2 inhibitor, demonstrates superior anti-tumor activity in CCNE1 high-expression solid tumor models
Authors: Chengshan Niu, Meihua Li, Shaoqing Chen, Maolin Zheng, Mingtao Chen, Hui Xu, Kaige Ji, Yuanjie Li, Rui Wu, Shengli Dong, Yu Yu, Xinlong Yang, Chao Zhou, Apeng Liang, Wei Wu, Mingyu Jiang, Jun Li, Yusheng Wu
Journal: Cancer Research (2025)

Abstract Background: The common prescription of Palbociclib and other approved CDK4/6 inhibitors in clinic have greatly benefitted breast cancer patients worldwide. The cell cycle regulation therapy however has been found that the long-term use of the CDK4/6 inhibition agents eventually causes primary or acquired resistance to the therapy, and patients eventually relapse from the treatment. Approximately 20% of patients treated with CDK4/6 inhibitors show initial treatment failure. Based on the finding that abnormal activation of CDK2/Cyclin E1 due to CCNE1 gene amplification is determined the key resistant mechanism to CDK4/6 inhibition. Amplification of CCNE gene is prevalent in multiple tumor types, particularly in high-grade ovarian, uterine, and gastric cancers. CDK2 activity is important for survival of CCNE aberrant cancer cells and is also associated with potential resistance to targeted therapies, such as CDK4/6 dual inhibitors. Therefore, CDK2 is a promising therapeutic target in cancer. However, due to the structural homology and functional conservation of CDK family members, as well as the toxic effects associated with the inhibition of other CDKs, the development of selective CDK2 inhibitor is challenging. Here, we present preclinical data of TY-1781, a novel CDK2 inhibitor for the treatment of CCNE1 high-expression tumors. Results: TY-1781 demonstrates excellent CDK2 kinase inhibitory activity (IC50 0.7 nM), and high selectivity against CDK1, CDK4, CDK6, CDK7, and CDK9 in a panel screening of CDK kinases. In vitro cell proliferation data shows that tumor cell lines bearing CCNE1 amplification, are highly sensitive to the TY-1781 treatment. TY-1781 inhibits cellular Rb phosphorylation in Cyclin E1 amplified OVCAR3 cells in a potent yet selective manner, but not in Cyclin E1 wild type TOV21G cells; TY-1781 blocks the G1/S transition in CCNE1 overexpression OVCAR3 cells; and the tumor inhibitory activity of TY-1781 is further underscored when combined with a CDK4/6 inhibitor (Palbociclib), as demonstrated in a cell colony formation assay with ER+/Her2- breast cancer cells. Consistent with the in vitro results, TY-1781 demonstrated a potent inhibitory effect in immune-defect mouse models of CCNE1-amplified cancer cells. When combined with a chemotherapy agent (gemcitabine) or PARP inhibitor, TY-1781 robustly suppressed tumor growth in the examined ovarian cancer models. Conclusion: Taken together, we identified a highly selective and potent CDK2 inhibitor through medicinal chemistry screening and rounds of refining. The data suggest that TY-1781 may be eligible for further clinical development for Cyclin E1 high-expression patients who relapse from previous standard of care treatments. Citation Format: Chengshan Niu, Meihua Li, Shaoqing Chen, Maolin Zheng, Mingtao Chen, Hui Xu, Kaige Ji, Yuanjie Li, Rui Wu, Shengli Dong, Yu Yu, Xinlong Yang, Chao Zhou, Apeng Liang, Wei Wu, Mingyu Jiang, Jun Li, Yusheng Wu. TY-1781, a potent and highly selective CDK2 inhibitor, demonstrates superior anti-tumor activity in CCNE1 high-expression solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5338.