Abstract 4736: A highly selective CDK4/9 dual inhibitor reverses tumor resistance to CDK4/6 inhibitors

Abstract Background: CDK4/6 inhibitors have been approved for the treatment of metastatic ER+ and HER2- breast cancer. However, patients will become resistance due to various mechanisms, resulting in high unmet need. Literature suggests that CDK9 activity may be involved in the mechanism of resistance to CDK4/6 inhibitors, and targeting CDK9 could be an effective strategy to overcome breast cancer resistance. Methods and Materials: Using the Convalife "Right 6D+AI" molecular design platform, AI-based screening and multi-angle evaluation were conducted on over 8, 000 virtual molecules, ultimately yielding candidate molecule N049 with selectivity for CDK4 and CDK9 that were >30-fold and >80-fold higher than for CDK6, respectively. To explore the therapeutic potential of N049 in palbociclib-resistant tumors, effects on cell viability were evaluated in both palbociclib-sensitive and -resistant cell lines. Additionally, patient-derived organoids (PDOs) and PDX models were used to assess the impact of CDK4/9 inhibitors on cell viability. Results: The CDK4/9 inhibitor N049 targeting CDK9 significantly impaired the viability of both palbociclib-sensitive and palbociclib-resistant LTED cell lines. Furthermore, in patient-derived organoids (PDOs) and PDX models, the CDK9 inhibitor drove tumor regression in palbociclib-resistant PDXs. Conclusion: Our findings suggest that simultaneous inhibition of CDK4 and CDK9 may exert potential synergistic effects to overcome CDK4/6 inhibitor resistance. The use of CDK4/9 inhibitors N049 could be an effective strategy to address resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. CDK4/9 inhibitors N049 represent a promising therapeutic approach for overcoming breast cancer resistance. Citation Format: Jinwen Huang, Zhongyuan Li, Zeng Song, Yunli Liu, Steve Shen. A highly selective CDK4/9 dual inhibitor reverses tumor resistance to CDK4/6 inhibitors [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 4736.