School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China.
School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China.
Eur J Med Chem. 2018 Sep 5;157:935-945. doi: 10.1016/j.ejmech.2018.08.043. Epub 2018 Aug 18.
CDK4/6 pathway is an attractive target for development of anti-cancer drugs. Herein, we reported the design and synthesis of a series of 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives as selective CDK4/6 inhibitors. Applied with the optimizing strategy to the initial scaffold, it is found that compound 13n is able to selectively inhibit CDK4 and CDK6 with IC values 0.01 and 0.026 μM, respectively. The compound showed good anti-proliferative activity when tested in a panel of tumor cell lines with CDK4/6 related mechanism of action, the results clearly suggest that compound 13n works much better than Ly2385219 which is a selective CDK4/6 inhibitor. This compound was also found to have favorable pharmacokinetic parameters. Taken together, compound 13n could be selected for further preclinical evaluation.
CDK4/6 通路是开发抗癌药物的一个有吸引力的靶点。本文报道了一系列 4,5-二氢-1H-吡唑并[4,3-h]喹唑啉衍生物的设计与合成，这些化合物作为选择性 CDK4/6 抑制剂。通过对初始支架应用优化策略，发现化合物 13n 能够选择性地抑制 CDK4 和 CDK6，IC 值分别为 0.01 和 0.026 μM。在具有 CDK4/6 相关作用机制的肿瘤细胞系中进行测试时，该化合物表现出良好的抗增殖活性，结果清楚地表明化合物 13n 的效果明显优于 Ly2385219，后者是一种选择性 CDK4/6 抑制剂。该化合物还被发现具有良好的药代动力学参数。综上所述，化合物 13n 可以被选择进行进一步的临床前评估。
