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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)540-545
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume9
Issue number6
DOIs
Publication statusPublished - 2018 Jun 14

Keywords

  • CDK19
  • CDK8
  • Cereblon
  • Cortistatin A
  • E3 ligase
  • PROTAC
  • degradation
  • kinase inhibitor
  • mediator complex

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Hatcher, J. M., Wang, E. S., Johannessen, L., Kwiatkowski, N., Sim, T., & Gray, N. S. (2018). Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8. ACS Medicinal Chemistry Letters, 9(6), 540-545. https://doi.org/10.1021/acsmedchemlett.8b00011