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

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

Affiliations

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

John M Hatcher et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Overlay of 19 (yellow) with Cortistatin A (cyan).
Scheme 1
Scheme 1. Preparation of Compounds 116
Reagents and conditions: (a) Pd(PPh3)2Cl2, isoquinolin-7-ylboronic acid, Na2CO3, dioxane/H2O, 80%; (b) KOOCN=NCOOK, AcOH, DMSO, THF, 60%.
Scheme 2
Scheme 2. Preparation of Compounds 1820
Reagents and conditions: (a) ethylene glycol, toluene, TsOH, 100 °C, 98%; (b) DPPA, DEAD, PPh3, THF, 87%; (c) trimethylphosphine, THF/H2O, 85%; (d) formaldehyde, EtOAc, MeOH, 92%; (e) TsOH, acetone, 98%; (f) KHMDS, PhN(SO2CF3)2, THF, 95%; (g) Pd(PPh3)2Cl2, 7-isoquinoline boronic acid, Na2CO3, dioxane/H2O, 76%; (h) KOOCN=NCOOK, AcOH, DMSO, THF, 70%.
Figure 2
Figure 2
Molecular model of JH-VIII-49 with CDK8.
Figure 3
Figure 3
Kinomescan results for JH-VIII-49 at a concentration of 10 μM with a cutoff of 90% inhibition.
Figure 4
Figure 4
Structure of PROTAC compounds and biochemical IC50s.
Figure 5
Figure 5
Cellular evaluation of the bivalent degrader molecules. (A) Jurkat cells were treated with 0.1 and 1 μM compounds 28 and 29; lysates were analyzed at 6 and 24 h for CDK8 levels by immunoblot. (B) WT Molt4 and CRBN null Molt4 cells were treated with increasing concentrations of 29; lysates were analyzed at 24 h for CDK8 levels by immunoblot. (C) Jurkat cells were treated with increasing concentrations of 30, and CDK8 levels were analyzed after 24 h by immunoblot. (D) Jurkat cells were treated with increasing concentrations of negative control 31, and CDK8 levels were analyzed after 24 h by immunoblot.

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