Abstract 1905: Discovery of ABK-CDK4, a selective and brain-penetrant CDK4 inhibitor.

Abstract Introduction: Cyclin-dependent kinase (CDK)4/6 play important roles in the G1-S phase transition in the cell cycle. Although the first generation dual CDK4/6 inhibitors— such as palbociclib, ribociclib, and abemaciclib—have demonstrated clinical efficacy in advanced breast cancer, inhibition of CDK6 would cause dose-limiting hematological toxicity. Sparing CDK6 inhibition could improve therapeutic window and enhance CDK4 target coverage. Meanwhile, brain metastases occur in 20%-40% of patients with breast cancer during their course of disease. A selective CDK4 inhibitor with reduced CDK6 inhibition and good brain penetration could provide a differentiated therapeutic option, especially for patients with brain metastasis. Through advanced computational structural analysis and medicinal chemistry effort, we have discovered ABK-CDK4, a highly selective and brain-penetrant CDK4 inhibitor. Preclinical studies demonstrate its good selectivity over CDK6, robust anti-tumor efficacy, and favorable pharmacokinetics. Methods: Biochemical assays were performed to assess the potency of ABK-CDK4 against CDK4 and to evaluate selectivity across a kinase panel, including CDK6. Anti-proliferative effect and inhibition of retinoblastoma (Rb) phosphorylation were tested in multiple cancer cell lines. In vivo anti-tumor activity was evaluated in cell-derived xenograft (CDX) mouse models. Pharmacokinetic and safety profiles were also examined. Results: ABK-CDK4 exhibited potent inhibition of CDK4 with 70-fold selectivity over CDK6. In HR+HER2- cancer cell lines, it effectively suppressed Rb phosphorylation and cell proliferation. ADME profiling demonstrated superior brain-penetration (Kpuu0.5) and favorable drug-like properties. Orally administration of ABK-CDK4 led to robust tumor growth inhibition in HR+HER2- breast cancer xenograft models. Conclusion: ABK-CDK4, developed by Abbisko Therapeutics, is a highly selective and brain-penetrant CDK4 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 Zhang, Jie Wang, Manqi Zhang, Haibing Deng, Hongping Yu, Yao-chang Xu, Haiyan Ying. Discovery of ABK-CDK4, a selective and brain-penetrant CDK4 inhibitor 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 1905.