Abstract 5329: Development of a novel selective CDK4 inhibitor for HR+/HER2- breast cancer

Abstract Introduction: FDA approved CDK4/6 inhibition medicines has demonstrated significant clinical benefits in patients with HR+/HER2- breast cancer. However, the dual CDK4/6 inhibitors also present severe on-target toxicity leading to severe adverse effects (SAE) in the clinic, such as neutropenia. Clinical studies with palbociclib reported grade 3-4 neutropenia events in 60-66% of patients receiving the treatment. To dissect the cause of the clinical toxicity of CDK4/6, it has been found that CDK6, not CDK4, is directly involved in the differentiation of myeloid cell in which CDK6 expression is up-regulated. Thus, we sought to develop a mono-CDK targeting agent, a CDK4 inhibitor, to grant similar pharmacological potency against HR+/HER2- breast cancer while diminishing or even abolishing CDK6 on-target toxicity to improve the efficacy, and more importantly, the safety of the hallmark cell cycle therapies. To this end, we at TYK Medicines have developed lead CDK4 inhibitor candidates (TY-2072) with high selectivity and potency. Results: TY-2072 demonstrates high selectivity against CDK4, and more than 17-fold selectivity against CDK6 compared to palbociclib, proving that TY-2072 is a CDK4 inhibitor rather than a CDK4/6 dual inhibitor. Western blot assays showed a dose-dependent reduction in phosphorylated RB (Ser780) in breast cancer cell lines after 48 hours TY-2072 treatment. The anti-proliferation effects of CDK4 inhibitors were assessed with MCF7 (breast cancer, CDK4 sensitive), JEKO-1 (mantle cell lymphoma), and MOLM13 (acute myeloid leukemia, CDK6 sensitive) through a CTG cell viability assay after 5-day incubation. Palbociclib shows a strong inhibitory effect on MCF7/T47D cells due to dual CDK4 and CDK6 kinase activity. TY-2072 strongly inhibited JEKO-1, but had no inhibitory effect on CDK6 high-expression MOLM13. In MCF7-xenograft mouse model, TY-2072 showed significant suppression of tumor growth in a dose-dependent manner at 20 and 40 mg/kg BID, TY-2072 exhibited synergetic effects with Fulvestrant on anti-tumor growth inhibition with good tolerance, evidenced by the maintenance of body weight of the animals throughout the study. We conducted preliminary in vitro combination studies with lead CDK4 compounds, and the combination of a selective CDK4 inhibitor with a CDK2 inhibitor or a PI3K inhibitor demonstrated a significant synergistic inhibitory effect on MCF7 cells and MCF7 Palbociclib-resistant cells. Positive results were also observed when TY-2072 was combined with AMG510/MRTX849 in the NSCLC H2122 (KRAS G12C) cells. In summary, the optimization of the lead compounds is continuing with goal to identify a PCC compound in the near future for IND-enabling studies. Citation Format: Mei Hua Li, Apeng Liang, Kai Wang, Yi Long, Rui Wu, Hui Xu, Jian Zhu, Guangbin Liu, Ling Fang, Xi Wang, Chenjie Pan, Yiming Cai, Xiang Zhang, Shengli Dong, Yu Yu, Xinlong Yang, Chao Zhou, Wei Wu, Chengshan Niu, Mingyu Jiang, Shaoqing Chen, Jun Li, Yusheng Wu. Development of a novel selective CDK4 inhibitor for HR+/HER2- breast cancer [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 5329.