Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8

John M Hatcher; Eric S Wang; Liv Johannessen; Nicholas Kwiatkowski; Taebo Sim; Nathanael S Gray

doi:10.1021/acsmedchemlett.8b00011

Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8

ACS Med Chem Lett. 2018 Mar 18;9(6):540-545. doi: 10.1021/acsmedchemlett.8b00011. eCollection 2018 Jun 14.

Authors

John M Hatcher^{1

2}, Eric S Wang^{1

2}, Liv Johannessen^{1

2}, Nicholas Kwiatkowski^{1

2}, Taebo Sim³, Nathanael S Gray^{1

2}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
² Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
³ Chemical Kinomics Research Center, KU-KIST, Korea Institute of Science and Technology, Seoul 136-791, Korea.

Abstract

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.