Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8,ACS Medicinal Chemistry Letters

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Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-03-18 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00011
John M. Hatcher _{1,

2} , Eric S. Wang _{1,

2} , Liv Johannessen _{1,

2} , Nicholas Kwiatkowski _{1,

2} , Taebo Sim ₃ , Nathanael S. Gray _{1,

2}

Affiliation

Cortistatin A is a natural product isolated from the marine sponge Corticium simplex and was found to be a potent and selective inhibitor of CDK8. Many synthetic groups have reported total syntheses of Cortistatin A; however, these syntheses require between 16 and 30 steps and report between 0.012–2% overall yields, which is not amenable to large-scale production. Owing to similarities between the complex core of Cortistatin A and the simple steroid core, we initiated a campaign to design simple, more easily prepared CDK8 inhibitors based on a steroid scaffold that would be more convenient for large-scale synthesis. Herein, we report the discovery and optimization of JH-VIII-49, a potent and selective inhibitor of CDK8 with a simple steroid core that has an eight-step synthesis with a 33% overall yield, making it suitable for large-scale preparation. Using this scaffold, we then developed a bivalent small molecule degrader, JH-XI-10-02, that can recruit the E3 ligase CRL4^Cereblon to promote the ubiquitination and proteosomal degradation of CDK8.

中文翻译：

CDK8高强度和选择性类固醇抑制剂和降解剂的开发

Cortistatin A是从海洋海绵Corticium simplex分离的天然产物，被发现是CDK8的有效和选择性抑制剂。许多合成群体报告了皮质抑素A的全部合成。但是，这些合成需要16到30个步骤，并且报告的总收率介于0.012–2％之间，因此不适合大规模生产。由于Cortistatin A的复杂核心与简单的类固醇核心之间的相似性，我们发起了一场运动，以基于类固醇骨架的简单，更容易制备的CDK8抑制剂的设计，这将更便于大规模合成。在此，我们报告了JH-VIII-49的发现和优化，JH-VIII-49是具有简单类固醇核心的强效选择性CDK8抑制剂，具有八步合成，总产率为33％，适用于大规模制备。然后，使用该支架，我们开发了一种二价小分子降解物JH-XI-10-02，它可以募集E3连接酶CRL4^小脑促进^CDK8的泛素化和蛋白体降解。

更新日期：2018-03-18

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