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Cell Chem Biol. 2019 Jun 20;26(6):792-803.e10. doi: 10.1016/j.chembiol.2019.02.012. Epub 2019 Mar 21.

Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biology Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Therapeutic Innovation Center (THINC@BCM), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biology Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
3
Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
4
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
5
Laboratory of Systems Pharmacology, Harvard Medical School, Boston MA 02115, USA.
6
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biology Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
7
Institute of Structural Biology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
8
Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Korea.
9
Therapeutic Innovation Center (THINC@BCM), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
10
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biology Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: nicholasp_kwiatkowski@dfci.harvard.edu.
11
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biology Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: nathanael_gray@dfci.harvard.edu.

Abstract

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:

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

PMID:
30905681
PMCID:
PMC6588464
[Available on 2020-06-20]
DOI:
10.1016/j.chembiol.2019.02.012

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