Cell Chemical Biology
Volume 26, Issue 6, 20 June 2019, Pages 792-803.e10
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Article
Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype

https://doi.org/10.1016/j.chembiol.2019.02.012Get rights and content
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Highlights

  • Development of YKL-5-124 a potent, selective and covalent CDK7 inhibitor

  • Selective CDK7 inhibition results in cell-cycle inhibition rather than apoptosis

  • YKL-5-124 exhibited little effect on RNA polymerase II phosphorylation status

Summary

Cyclin-dependent kinase 7 (CDK7) regulates both cell cycle and transcription, but its precise role remains elusive. We previously described THZ1, a CDK7 inhibitor, which dramatically inhibits superenhancer-associated gene expression. However, potent CDK12/13 off-target activity obscured CDK7s contribution to this phenotype. Here, we describe the discovery of a highly selective covalent CDK7 inhibitor. YKL-5-124 causes arrest at the G1/S transition and inhibition of E2F-driven gene expression; these effects are rescued by a CDK7 mutant unable to covalently engage YKL-5-124, demonstrating on-target specificity. Unlike THZ1, treatment with YKL-5-124 resulted in no change to RNA polymerase II C-terminal domain phosphorylation; however, inhibition could be reconstituted by combining YKL-5-124 and THZ531, a selective CDK12/13 inhibitor, revealing potential redundancies in CDK control of gene transcription. These findings highlight the importance of CDK7/12/13 polypharmacology for anti-cancer activity of THZ1 and posit that selective inhibition of CDK7 may be useful for treatment of cancers marked by E2F misregulation.

Keywords

transcription
gene expression
cell cycle
drug discovery
cancer
small-molecule inhibitor

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These authors contributed equally

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