Jiang Chenran, Ye Yuxin, Kang Wei, Yang Jinglei, He Zhipeng, Cao Qixiong, Lian Chenshan, Xing Yajie, Yang Qianqian, Zhao Juan, Pan Shuqiong, Feng Meixi, Song Chunli, Liu Zhihong, Wang Rui, Yin Feng, Wu Yun-Dong, Chen Jiean, Huang Yong
Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518118, China.
J Med Chem. 2025 Jan 23;68(2):1499-1510. doi: 10.1021/acs.jmedchem.4c01686. Epub 2025 Jan 4.
CDK4/6 inhibitors are effective in treating HR/HER2 breast cancer but face limitations due to therapeutic resistance and hematological toxicity, particularly from strong CDK6 inhibition. To address these challenges, designing selective inhibitors targeting specific cyclin-dependent kinases (CDK) members could offer clinical advantages and broaden CDK inhibitor indications. However, the highly conserved binding pockets of CDKs complicate selective targeting. This study leverages in silico modeling and structural analysis of cocrystal data to identify subtle differences in key CDK binding pockets. Notably, a sequence difference in the αD-helix motif between CDK4 and CDK6 provides a targetable "sweet spot" for selectivity. By incorporating a 1,4-trans-cyclohexanediamine side chain, we designed molecules that favor interactions with CDK4 over CDK6 and explored potential dual CDK4/9 inhibition. This approach yielded a lead compound with distinct in vitro selectivity and promising in vivo pharmacokinetics, offering valuable insights for the development of selective next-generation CDK inhibitors.
细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂在治疗激素受体（HR）阳性/人表皮生长因子受体2（HER2）阴性乳腺癌方面有效，但由于治疗耐药性和血液学毒性，尤其是强效CDK6抑制所导致的毒性，其应用面临局限。为应对这些挑战，设计靶向特定细胞周期蛋白依赖性激酶（CDK）成员的选择性抑制剂可能具有临床优势，并拓宽CDK抑制剂的适应症。然而，CDK高度保守的结合口袋使选择性靶向变得复杂。本研究利用计算机模拟建模和共晶体数据的结构分析，以识别关键CDK结合口袋中的细微差异。值得注意的是，CDK4和CDK6之间αD-螺旋基序的序列差异为选择性提供了一个可靶向的“甜点”。通过引入1,4-反式环己二胺侧链，我们设计了更倾向于与CDK4而非CDK6相互作用的分子，并探索了潜在的CDK4/9双重抑制作用。这种方法产生了一种具有独特体外选择性和有前景的体内药代动力学的先导化合物，为开发选择性下一代CDK抑制剂提供了有价值的见解。
