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

Title
Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
Authors
심태보John M. HatcherEric S. WangLiv JohannessenNicholas KwiatkowskiNathanael S. Gray
Issue Date
2018-06
Publisher
ACS MEDICINAL CHEMISTRY LETTERS
Citation
VOL 9, NO 6-545
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(cerebion) to promote the ubiquitination and proteosomal degradation of CDK8.
URI
http://pubs.kist.re.kr/handle/201004/68072
ISSN
1948-5875
Appears in Collections:
KIST Publication > Article
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