Wang Yan, Liu Wen-Jian, Yin Lei, Li Heng, Chen Zhen-Hua, Zhu Dian-Xi, Song Xiu-Qing, Cheng Zhen-Zhen, Song Peng, Wang Zhan, Li Zhi-Gang
Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing 100124, PR China; Gan&lee Pharmaceuticals R&D, No.8 Jingsheng North 3rd Street, Majuqiao Town, Tongzhou, Beijing 101102, PR China.
Gan&lee Pharmaceuticals R&D, No.8 Jingsheng North 3rd Street, Majuqiao Town, Tongzhou, Beijing 101102, PR China.
Bioorg Med Chem Lett. 2018 Mar 1;28(5):974-978. doi: 10.1016/j.bmcl.2017.12.068. Epub 2018 Jan 31.
Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as anticancer drugs.
细胞周期蛋白依赖性激酶4/6在细胞周期调控中起重要作用，且在多种癌症中过表达。到目前为止，由于其选择性差，仍需要开发新的CDK抑制剂。在此，我们报道了一系列基于LY2835219（阿贝西利）的新型4-(2,3-二氢-1H-苯并[d]吡咯并[1,2-a]咪唑-7-基)-N-(5-(哌嗪-1-基甲基)吡啶-2-基)嘧啶-2-胺类似物，作为有效的CDK 4/6抑制剂。化合物10d对CDK4/6表现出近似的活性（IC = 7.4/0.9 nM），与LY2835219相比，具有良好的药代动力学特征和对CDK1的高选择性。总体而言，化合物10d可能是一种有前景的候选物，也是作为抗癌药物的良好起点。
