Discovery of Covalent MKK4/7 Dual Inhibitor

  • Cell Chem Biol. 2020 Dec 17;27(12):1553-1560.e8. doi: 10.1016/j.chembiol.2020.08.014.
Jie Jiang  1 ,  Baishan Jiang  1 ,  Zhixiang He  1 ,  Scott B Ficarro  2 ,  Jianwei Che  1 ,  Jarrod A Marto  3 ,  Yang Gao  1 ,  Tinghu Zhang  4 ,  Nathanael S Gray  5
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
  • 5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 32916088 DOI: 10.1016/j.chembiol.2020.08.014
Abstract

MKK4/7 are kinases that phosphorylate JNKs and regulate the MAPK signaling pathway. Their overexpression has been associated with tumorigenesis and aggressiveness in cancers such as breast, prostate, non-small cell lung, and pediatric leukemia, making them a potential target for inhibitor development. Here, we report the discovery, development, and validation of a dual MKK4/7 inhibitor, BSJ-04-122, that covalently targets a conserved cysteine located before the DFG motif and displays excellent kinome selectivity. BSJ-04-122 exhibits potent cellular target engagement and induces robust target-specific downstream effects. The combination of the dual MKK4/7 inhibitor with a selective, covalent JNK Inhibitor demonstrated an enhanced antiproliferative activity against triple-negative breast Cancer cells. Taken together, the results show that BSJ-04-122 represents a pharmacological probe for MKK4/7 and credential covalent targeting as a way to explore the therapeutic potential of these kinases.

Keywords
MKK4/7; breast cancer; small-molecule kinase inhibitor; target therapy.
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