2. Academic Validation
  3. Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13

Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13

  • J Med Chem. 2020 Jul 9;63(13):6708-6726. doi: 10.1021/acs.jmedchem.9b01929.
Yao Liu 1 2,  Mingfeng Hao 1 2,  Alan L Leggett 1 2,  Yang Gao 1 2,  Scott B Ficarro 1 2 3,  Jianwei Che 1 2,  Zhixiang He 1 2,  Calla M Olson 1 2,  Jarrod A Marto 1 2 3,  Nicholas P Kwiatkowski 1 2,  Tinghu Zhang 1 2,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 2 Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  • 3 Blais Proteomics Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, United States.
PMID: 32502343 DOI: 10.1021/acs.jmedchem.9b01929
Abstract

Genetic depletion of cyclin-dependent kinase 12 (CDK12) or selective inhibition of an analog-sensitive CDK12 reduces DNA damage repair gene expression, but selective inhibition of endogenous CDK12 is difficult. Here, we report the development of MFH290, a novel cysteine (Cys)-directed covalent inhibitor of CDK12/13. MFH290 forms a covalent bond with Cys-1039 of CDK12, exhibits excellent kinome selectivity, inhibits the phosphorylation of serine-2 in the C-terminal domain (CTD) of RNA-polymerase II (Pol II), and reduces the expression of key DNA damage repair genes. Importantly, these effects were demonstrated to be CDK12-dependent as mutation of Cys-1039 rendered the kinase refractory to MFH290 and restored Pol II CTD phosphorylation and DNA damage repair gene expression. Consistent with its effect on DNA damage repair gene expression, MFH290 augments the antiproliferative effect of the PARP Inhibitor olaparib.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153244
    98.07%, CDK12/13 Inhibitor
    CDK