Abstract A092: Discovery of ABK-CDK-1, a selective and brain penetrant CDK4/2 inhibitor to overcome resistance of CDK4/6 inhibitors in breast cancer

Abstract Introduction: Cyclin-dependent kinase (CDK)4/6 inhibitors have demonstrated clinical efficacy in advanced breast cancer and their application has also been expanded into early-stage disease with large patient population. However, the clinical benefit of first-generation CDK4/6 inhibitors—such as palbociclib, ribociclib, and abemaciclib—is limited by CDK6-mediated toxicity and the emergence of resistance driven in part by cyclin E/CDK2 activation. A selective CDK4/2 inhibitor that spares CDK6 and penetrates the blood–brain barrier could provide a differentiated therapeutic option, especially for patients with brain metastases or resistance to existing CDK4/6 inhibitors. Through advanced computational structural analysis and medicinal chemistry effort, we have developed ABK-CDK-1, a novel, selective and brain-penetrant CDK4/2 inhibitor. Preclinical studies demonstrate its good selectivity over CDK6, strong potency in palbociclib-resistant models, robust anti-tumor efficacy, and favorable drug-like properties. Methods: Biochemical assays were performed to assess the potency of ABK-CDK-1 against CDK2 and CDK4 and to evaluate selectivity across a kinase panel, including CDK6. Anti-proliferative effects and inhibition of retinoblastoma (Rb) phosphorylation were tested in multiple cancer cell lines. The efficacy against CDK4/6 inhibitor resistance was assessed using palbociclib-resistant ER+ breast cancer cells. In vivo anti-tumor activity was evaluated in cell-derived xenograft (CDX) mouse models. Pharmacokinetic and safety profiles were also examined. Results: ABK-CDK-1 exhibited potent inhibition of CDK4 with >40-fold selectivity over CDK6 in biochemical assays. In CDK4-dependent cancer cell lines, it effectively suppressed proliferation and Rb phosphorylation. ABK-CDK-1 also strongly inhibited CDK2, resulting in significant anti-proliferative activity in cyclin E/CDK2-driven cell models. Importantly, it retained activity in palbociclib-resistant breast cancer cells. ADME profiling demonstrated good brain-penetration and favorable drug-like properties. Oral administration of ABK-CDK-1 led to robust tumor growth inhibition in xenograft models, with no significant toxicity observed. Conclusion: ABK-CDK-1, developed by Abbisko Therapeutics, is a novel selective and brain-penetrant CDK4/2 inhibitor with the potential to address limitations of current CDK4/6 inhibitors. Its promising efficacy, selectivity, and other properties support further preclinical advancement toward clinical development. Citation Format: Weiling Pan, Hui Wang, Fangfei Qi, Zheng Li, Xinming Du, Jie Wang, Jie Zhang, Manqi Liu, Haibing Deng, Hongping Yu, Yao-chang Xu, Haiyan Ying. Discovery of ABK-CDK-1, a selective and brain penetrant CDK4/2 inhibitor to overcome resistance of CDK4/6 inhibitors in breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A092.