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

Kristine K. Deibler, Gary E. Schiltz, Matthew R. Clutter, Rama K. Mishra, Purav P. Vagadia, Matthew O'Connor, Mariam Donny George, Ryan Gordon, Graham Fowler, Raymond Bergan, Karl A. Scheidt

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalChemMedChem
DOIs
StatePublished - Jan 1 2019

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MAP Kinase Kinase 4
Benzoic Acid
Molecular modeling
Oncology
p38 Mitogen-Activated Protein Kinases
Prostatic Neoplasms
Phosphotransferases
Neoplasm Metastasis
mitogen-activated protein kinase kinase kinase 12

Keywords

  • antitumor agents
  • indazoles
  • kinases
  • MEK4
  • prostate cancer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Deibler, K. K., Schiltz, G. E., Clutter, M. R., Mishra, R. K., Vagadia, P. P., O'Connor, M., ... Scheidt, K. A. (2019). Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors. ChemMedChem. https://doi.org/10.1002/cmdc.201900019

Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors. / Deibler, Kristine K.; Schiltz, Gary E.; Clutter, Matthew R.; Mishra, Rama K.; Vagadia, Purav P.; O'Connor, Matthew; George, Mariam Donny; Gordon, Ryan; Fowler, Graham; Bergan, Raymond; Scheidt, Karl A.

In: ChemMedChem, 01.01.2019.

Research output: Contribution to journalArticle

Deibler, KK, Schiltz, GE, Clutter, MR, Mishra, RK, Vagadia, PP, O'Connor, M, George, MD, Gordon, R, Fowler, G, Bergan, R & Scheidt, KA 2019, 'Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors', ChemMedChem. https://doi.org/10.1002/cmdc.201900019
Deibler KK, Schiltz GE, Clutter MR, Mishra RK, Vagadia PP, O'Connor M et al. Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors. ChemMedChem. 2019 Jan 1. https://doi.org/10.1002/cmdc.201900019
Deibler, Kristine K. ; Schiltz, Gary E. ; Clutter, Matthew R. ; Mishra, Rama K. ; Vagadia, Purav P. ; O'Connor, Matthew ; George, Mariam Donny ; Gordon, Ryan ; Fowler, Graham ; Bergan, Raymond ; Scheidt, Karl A. / Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors. In: ChemMedChem. 2019.
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