Discovery of Covalent MKK4/7 Dual Inhibitor

Jie Jiang; Baishan Jiang; Zhixiang He; Scott B Ficarro; Jianwei Che; Jarrod A Marto; Yang Gao; Tinghu Zhang; Nathanael S Gray

doi:10.1016/j.chembiol.2020.08.014

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.

Authors

Jie Jiang¹, Baishan Jiang¹, Zhixiang He¹, Scott B Ficarro², Jianwei Che¹, Jarrod A Marto³, Yang Gao¹, Tinghu Zhang⁴, Nathanael S Gray⁵

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.

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*

Substances

Protein Kinase Inhibitors
MAP Kinase Kinase 4
MAP Kinase Kinase 7