Hatcher John M, Wang Eric S, Johannessen Liv, Kwiatkowski Nicholas, Sim Taebo, Gray Nathanael S
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
ACS Med Chem Lett. 2018 Mar 18;9(6):540-545. doi: 10.1021/acsmedchemlett.8b00011. eCollection 2018 Jun 14.
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 to promote the ubiquitination and proteosomal degradation of CDK8.
皮质抑素A是从海洋海绵简单皮质海绵中分离出的一种天然产物，被发现是一种有效的、选择性的细胞周期蛋白依赖性激酶8（CDK8）抑制剂。许多合成团队都报道了皮质抑素A的全合成；然而，这些合成需要16至30步反应，总产率在0.012%至2%之间，这不适用于大规模生产。由于皮质抑素A的复杂核心与简单甾体核心之间存在相似性，我们开展了一项研究，旨在设计基于甾体骨架的简单、更易于制备的CDK8抑制剂，这种抑制剂对于大规模合成会更方便。在此，我们报告了JH-VIII-49的发现与优化，它是一种具有简单甾体核心的有效的、选择性的CDK8抑制剂，其合成路线为八步反应，总产率为33%，使其适合大规模制备。利用这个骨架，我们随后开发了一种二价小分子降解剂JH-XI-10-02，它可以招募E3泛素连接酶CRL4来促进CDK8的泛素化和蛋白酶体降解。
