State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
School of Pharmacy, Henan University, Kaifeng 475000, China.
Eur J Med Chem. 2021 Jul 5;219:113432. doi: 10.1016/j.ejmech.2021.113432. Epub 2021 Apr 3.
Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.
细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）参与细胞周期的动态调节，在控制肿瘤生长方面发挥着不可或缺的作用。在这里，我们基于 palbociclib 的支架，设计并合成了一系列靶向氨基酸 Thr107 的共价 CDK4/6 抑制剂。优化后的化合物 C-13 对 CDK4/6 表现出强大的体外抗癌活性，对 CDK4/6 具有高选择性。此外，C-13 在 MDA-MB-231 肿瘤异种移植模型中表现出显著的肿瘤生长抑制作用（在 40mg/kg 剂量下 TGI 为 93.49%），在治疗期间没有导致明显的体重减轻和毒性。
