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. Epub 2020 Sep 10.


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.

MeSH terms

  • Amino Acid Motifs
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Humans
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • MAP Kinase Kinase 4 / chemistry
  • MAP Kinase Kinase 7 / antagonists & inhibitors*
  • MAP Kinase Kinase 7 / chemistry
  • Models, Molecular
  • Protein Kinase Inhibitors / pharmacology*


  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 7