CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC₅₀ values of 0.65, 0.70, 0.39, and 2.53 μM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC₅₀ = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATP binding sites of CDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Taken together, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.

CDK4/6 已被确认为癌症治疗靶点。在这里，我们描述了一系列 pteridin-7(8H)-one 类似物作为有效的 CDK4/6 抑制剂。其中，最有前景的化合物7s对 HCT116、HeLa、MDA-MB-231 和 HT-29 细胞表现出显着的广谱抗增殖活性，IC ₅₀值分别为 0.65、0.70、0.39 和 2.53 μM，其中比抗癌药物 Palbociclib 更有效。有趣的是，7s还表现出对 CDK4/cyclin D3 和 CDK6/cyclin D3 的最大抑制活性（IC _{50 分别} 为 34.0 和 65.1 nM），这与 Palbociclib 相当。此外，分子模拟表明，7s在ATP结合有效的 结合 位点 的 CDK4和CDK6。进一步的机理研究表明，化合物7s可以浓度依赖性地诱导 HeLa 细胞的细胞周期停滞和凋亡。总之 ，7s代表了一种有前途的新型 CDK4/6 抑制剂，可用于癌症的潜在治疗。