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Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8.
Hatcher, John M; Wang, Eric S; Johannessen, Liv; Kwiatkowski, Nicholas; Sim, Taebo; Gray, Nathanael S.
Afiliación
  • Hatcher JM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • Wang ES; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
  • Johannessen L; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • Kwiatkowski N; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
  • Sim T; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • Gray NS; 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 ; 9(6): 540-545, 2018 Jun 14.
Article en En | MEDLINE | ID: mdl-29937979
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.

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos