2. Academic Validation
  3. Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype

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

  • Cell Chem Biol. 2019 Jun 20;26(6):792-803.e10. doi: 10.1016/j.chembiol.2019.02.012.
Calla M Olson 1,  Yanke Liang 2,  Alan Leggett 2,  Woojun D Park 3,  Lianbo Li 4,  Caitlin E Mills 5,  Selma Z Elsarrag 3,  Scott B Ficarro 6,  Tinghu Zhang 2,  Robert Düster 7,  Matthias Geyer 7,  Taebo Sim 8,  Jarrod A Marto 6,  Peter K Sorger 5,  Ken D Westover 4,  Charles Y Lin 9,  Nicholas Kwiatkowski 10,  Nathanael S Gray 11
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
PMID: 30905681 DOI: 10.1016/j.chembiol.2019.02.012
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101257B
    99.44%, CDK7 Inhibitor
    CDK