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.
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
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.
PMID: 29937979 DOI: 10.1021/acsmedchemlett.8b00011
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 CRL4Cereblon to promote the ubiquitination and proteosomal degradation of CDK8.

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