The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound 7 demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy in vitro, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor in vivo efficacy. Our findings indicate that compound 7 is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.

中文翻译：

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发现吡咯并嘧啶酮衍生物作为治疗癌症的有效 PKMYT1 抑制剂


蛋白激酶 PKMYT1 负责抑制性 CDK1 磷酸化，因此在调节 G2/M 细胞周期检查点中起核心作用。由于许多癌症具有功能失调的细胞周期检查点信号传导，因此 PKMYT1 抑制正在成为晚期肿瘤中一个有吸引力的靶点。然而，PKMYT1 抑制剂在平衡生物学疗效、靶向特异性、良好的稳定性和其他药物样特性方面遇到了困难。在此，我们报道了吡咯并嘧啶酮衍生物的设计和开发，旨在同时限制分子构象并屏蔽代谢位点以优化稳定性。化合物 7 在体外表现出强烈的 PKMYT1 特异性抑制、随后 CDK1 磷酸化降低和体外抗肿瘤功效，以及增强的代谢稳定性、良好的药代动力学和生物利用度特性，以及有效的体内抗肿瘤疗效。我们的研究结果表明，化合物 7 是一种很有前途的 PKMYT1 抑制剂，用于治疗具有细胞周期缺陷的晚期癌症。