Cyclin-dependent kinase 7 (CDK7) is a key regulator of the cell cycle and transcription, making it a promising target for cancer therapy. Although current CDK7 inhibitors have improved in their selectivity and druglike properties, CDK7 inhibitors have failed to progress through clinical development due to severe gastrointestinal and hematotoxic side effects. To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds 2 and 3 using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset. We conducted extensive structure–activity relationship (SAR) studies to improve their potency, enhance oral bioavailability, and reduce intestinal distribution, which resulted in compound 13. Compound 13 exhibits potent in vitro activity, good ADME properties, and robust in vivo antitumor activity in xenograft models as a monotherapy. Notably, compound 13 with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects.

中文翻译：

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用于癌症治疗的新型大环非共价 CDK7 抑制剂的发现


细胞周期蛋白依赖性激酶 7 （CDK7） 是细胞周期和转录的关键调节因子，使其成为癌症治疗的有前途的靶点。尽管目前的 CDK7 抑制剂的选择性和类药特性有所提高，但由于严重的胃肠道和血液毒性副作用，CDK7 抑制剂未能通过临床开发取得进展。为了减轻这些限制，我们使用大环化平台开发了新型、大环、非共价 CDK7 命化合物 2 和 3，该平台已从领先的临床资产 SY-5609 优化了这些化合物。我们进行了广泛的构效关系 （SAR） 研究，以提高其效力、提高口服生物利用度并减少肠道分布，从而产生了化合物 13。化合物 13 作为单一疗法在异种移植模型中表现出强大的体外活性、良好的 ADME 特性和强大的体内抗肿瘤活性。值得注意的是，碱度较低的化合物 13 表现出改善的 Caco-2 渗透性，降低血液/血浆比值，并减少大鼠的肠道分布，从而减轻胃肠道和血液毒性副作用。