Rational Design, Optimization, and Biological Evaluation of Novel MEK4 Inhibitors against Pancreatic Adenocarcinoma

Ada J. Kwong, Thao N.D. Pham, Hannah E. Oelschlager, Hidayatullah G. Munshi, Karl A. Scheidt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Growth, division, and development of healthy cells relies on efficient response to environmental survival cues. The conserved mitogen-activated protein kinase (MAPK) family of pathways interface extracellular stimuli to intracellular processes for this purpose. Within these pathways, the MEK family has been identified as a target of interest due to its clinical relevance. Particularly, MEK4 has drawn recent attention for its indications in pancreatic and prostate cancers. Here, we report two potent MEK4 inhibitors demonstrating significant reduction of phospho-JNK and antiproliferative properties against pancreatic cancer cell lines. Furthermore, molecular inhibition of MEK4 pathway activates the MEK1/2 pathway, with the combination of MEK1/2 and MEK4 inhibitors demonstrating synergistic effects against pancreatic cancer cells. Our inhibitors provided insight into the crosstalk between MAPK pathways and new tools for elucidating the roles of MEK4 in disease states, findings which will pave the way for better understanding of the MAPK pathways and development of additional probes.

Original languageEnglish (US)
Pages (from-to)1559-1567
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume12
Issue number10
DOIs
StatePublished - Oct 14 2021

Keywords

  • drug discovery
  • lead optimization
  • mitogen-activated protein kinases
  • pancreatic cancer
  • small molecule inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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