Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 10, Pages 1559-1567Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00376
Keywords
mitogen-activated protein kinases; drug discovery; small molecule inhibitors; lead optimization; pancreatic cancer
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Funding
- Lurie Research Innovation Challenge Award
- NIH [T32GM105538, F31CA250353]
- NIH/NCI [T32CA070085]
- Northwestern Undergraduate Research Grant
- Soft and Hybrid Nanotechnology Experiment (SHyNE) Resource [NSF ECCS-2025633]
- [R01CA217907]
- [R21CA255291]
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The study presents two potent MEK4 inhibitors which showed significant reduction in phospho-JNK and antiproliferative properties against pancreatic cancer cell lines. Additionally, molecular inhibition of the MEK4 pathway activates the MEK1/2 pathway, with the combination of MEK1/2 and MEK4 inhibitors demonstrating synergistic effects against pancreatic cancer cells. These inhibitors provide insight into the crosstalk between MAPK pathways and new tools for elucidating the roles of MEK4 in disease states.
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.
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