Abstract P4-10-06: Preclinical characterization of BGB-43395, a potential best-in-class CDK4 selective inhibitor with potent pharmacodynamic and anti-tumor activity in HR+HER2- breast cancer models

作者：Hengrui Zhu, Hanzi Sun, Wenqing Xu, Jing Li, Xiaoxin Liu, Tingting Zhang, Xudong Luan, Jing Wang, YingLiang Ma, Mingchao Kang, Shuran Li, Yilu Zhang, Chi Guan, Xin Li, Jingjing Meng, Jiyuan Zhang, Yao Yao, Zhirong Shen, Xiaomin Song, Fan Wang, Sean Lin, Yu Shen, Zhiwei Wang, Xuesong Liu, Lai Wang, Ye Liu · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1557-3265.sabcs24-p4-10-06 · 被引用次数：2 · 研究领域：Advanced Breast Cancer Therapies、HER2/EGFR in Cancer Research

Abstract Cyclin-dependent kinase (CDK) 4/6 inhibitors (palbociclib, ribociclib and abemaciclib) in combination with endocrine therapies have become the standard of care for patients with metastatic hormone receptor-positive, HER2-negative breast cancer (HR+HER2- BC). However, HR+HER2- BC is primarily dependent on CDK4, while CDK6 inhibition by dual CDK4/6 inhibitors often leads to dose-limiting neutropenia, which requires treatment holidays or dose reductions, thus limiting sustained CDK4 inhibition. Therefore, BGB-43395, a CDK4 selective inhibitor, was developed to reduce neutropenia by sparing CDK6, thereby maximizing CDK4 inhibition to further improve clinical benefit. BGB-43395 is a highly potent CDK4 kinase inhibitor with high selectivity over CDK6 and other CDK family kinases at biochemical level. In addition, BGB-43395 also demonstrated great selectivity against a panel of other kinases. These properties translated into a desirable toxicity profile in nonclinical toxicity studies, where BGB-43395 was well tolerated without concerning of neutropenia and gastrointestinal toxicity issues. In the biochemical assay, BGB-43395 exhibits superior kinase inhibition against CDK4 compared to approved CDK4/(6) inhibitors (palbociclib, ribociclib and abemaciclib) and investigational CDK4 inhibitor PF-07220060. The potency of BGB-43395 was further determined by RB1 phosphorylation inhibition in human breast cancer cell lines. Compared to PF-07220060 and approved CDK4/6 inhibitors, B...