2. Academic Validation
  3. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

  • Nat Chem Biol. 2016 Oct;12(10):876-84. doi: 10.1038/nchembio.2166.
Tinghu Zhang 1 2,  Nicholas Kwiatkowski 1 2 3,  Calla M Olson 1 2,  Sarah E Dixon-Clarke 4,  Brian J Abraham 3,  Ann K Greifenberg 5 6,  Scott B Ficarro 1 2 7,  Jonathan M Elkins 4,  Yanke Liang 1 2,  Nancy M Hannett 3,  Theresa Manz 1 8,  Mingfeng Hao 1 2,  Bartlomiej Bartkowiak 9,  Arno L Greenleaf 9,  Jarrod A Marto 1 2 7,  Matthias Geyer 5 6,  Alex N Bullock 4,  Richard A Young 3 10,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
  • 3 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
  • 4 Structural Genomics Consortium, University of Oxford, Oxford, UK.
  • 5 Department of Structural Immunology, Institute of Innate Immunity, University of Bonn, Bonn, Germany.
  • 6 Center of Advanced European Studies and Research, Bonn, Germany.
  • 7 Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 8 Pharmaceutical and Medicinal Chemistry, Department of Pharmacy, Saarland University, Saarbrücken, Germany.
  • 9 Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA.
  • 10 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
PMID: 27571479 DOI: 10.1038/nchembio.2166
Abstract

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and Cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify Cancer subtypes that are particularly dependent on their kinase activities.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-103618
    99.86%, CDK12/13 Inhibitor
    CDK