Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors

ChemMedChem. 2019 Mar 22;14(6):615-620. doi: 10.1002/cmdc.201900019. Epub 2019 Feb 19.

Abstract

Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signaling pathways that phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. Optimization of this series via structure-activity relationships and molecular modeling led to the identification of compound 6 ff (4-(6-fluoro-2H-indazol-3-yl)benzoic acid), a highly potent and selective MEK4 inhibitor. This series of inhibitors is the first of its kind in both activity and selectivity and will be useful in further defining the role of MEK4 in prostate and other cancers.

Keywords: MEK4; antitumor agents; indazoles; kinases; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Drug Evaluation, Preclinical
  • Humans
  • Indazoles / chemical synthesis*
  • Indazoles / pharmacology*
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Substrate Specificity

Substances

  • Indazoles
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human