选择性细胞周期蛋白依赖性激酶 4/6 抑制剂 (CDK4/6i) 彻底改变了乳腺癌的治疗方法，并且在其他癌症中具有潜力，是一种易于控制的药物，但具有一定的骨髓毒性。选择性CDK9抑制剂（CDK9i）从未进入临床使用，部分原因是副作用，包括胃肠道毒性，以及活性和细胞毒性之间的窗口较小，导致治疗指数（TI）狭窄。克服CDK4/6的缺点和 CDK9 抑制剂，我们开发了 myrtleciclib，一种选择性 CDK4/6/9 抑制剂，几乎没有非关键分子脱靶。Myrtleciclib 似乎与变构位点结合，与所有其他通过 ATP 竞争性作用的 CDK4/6i 和 CDK9i 不同机制，支持目标特异性。 Myrtleciclib 的抗增殖作用更强，其治疗指数 (TI) 比 CDK9 和 CDK4/6 抑制剂更广泛。这可以通过适度的靶标抑制来解释，从而导致有限的细胞毒性。此外，我们记录了 CDK9 和 CDK4/6 途径抑制之间的协同作用，证明了药物疗效的增加，但只有当 CDK9 和 CDK4/6 的抑制嵌入同一分子内并在一定比例内平衡时才能实现这种协同作用，就像 myrtleciclib 的情况一样。与 CDK4/6i 不同，myrtleciclib 还选择性地诱导癌细胞系而非旁观细胞的细胞死亡和凋亡。 myrtleciclib 与其他具有互补作用机制 (MoA) 的药物之间的协同作用也已被记录。CDK4/6/9i 可能代表癌症治疗的新领域，以克服 CDK4/6i 和 CDK9i 治疗癌症的局限性，包括侵袭性癌症癌症的需求未得到满足。版权所有© Bentham Science Publishers；如有任何疑问，请发送电子邮件至 epub@benthamscience.net。

Selective Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of breast cancer and have potential in other cancers, being manageable drugs yet with some bone marrow toxicity. Selective CDK9 inhibitors (CDK9i) never advanced into clinical use, partly due to side effects, including gastrointestinal toxicity, and a small window between activity and cytotoxicity, which results in a narrow therapeutic index (TI).To overcome the drawbacks of CDK4/6 and CDK9 inhibitors, we have developed myrtleciclib, a selective CDK4/6/9 inhibitor with few non-critical molecular off-targets.Myrtleciclib appears to bind to an allosteric site, unlike all other CDK4/6i and CDK9i acting by an ATP-competitive mechanism, which supports target specificity. Myrtleciclib's anti-proliferative effects are greater and its Therapeutic Index (TI) is broader than CDK9 and CDK4/6-only inhibitors. This can be explained by a moderate target inhibition, resulting in limited cytotoxicity. Moreover, we documented a synergy between CDK9 and CDK4/6 pathways inhibition, justifying increased drug efficacy, yet such synergy can only be achieved when the inhibition of both CDK9 and CDK4/6 is embedded within the same molecule and balanced within a certain ratio, as it is the case with myrtleciclib. Unlike CDK4/6i, myrtleciclib also induces cell death and apoptosis selectively on cancer cell lines, not on bystander cells. Synergy between myrtleciclib and other drugs with complementary Mechanism of Action (MoA) has also been documented.CDK4/6/9i might represent a new frontier in cancer treatment to overcome the limitations of CDK4/6i and CDK9i for the treatment of cancers, including aggressive cancers with high unmet needs.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.