TY - JOUR
T1 - Rational Design, Optimization, and Biological Evaluation of Novel MEK4 Inhibitors against Pancreatic Adenocarcinoma
AU - Kwong, Ada J.
AU - Pham, Thao N.D.
AU - Oelschlager, Hannah E.
AU - Munshi, Hidayatullah G.
AU - Scheidt, Karl A.
N1 - Funding Information:
This research was supported by the Lurie Research Innovation Challenge Award (to K.A.S. and H.G.M.) and grants R01CA217907 (to H.G.M.) and R21CA255291 (to H.G.M.). A.J.K. was supported by the NIH under award numbers T32GM105538 and F31CA250353. T.N.D.P. was supported by the NIH/NCI under award number T32CA070085. H.E.O. acknowledges support from the Northwestern Undergraduate Research Grant. This work made use of the High Throughput Analysis Laboratory at Northwestern University and the IMSERC NMR and MS facilities at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experiment (SHyNE) Resource (NSF ECCS-2025633). We also thank Matt Clutter (NU) and Michael Gullette (NU) for valuable discussion, and Saman Shafaie (NU) for assistance with high-resolution mass spectrometry. Kinome Tree image was generated using the TREE spot Software Tool and reprinted with permission from KINOME scan, a division of DiscoveRx Corporation, DISCOVERX CORPORATION 2010.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/10/14
Y1 - 2021/10/14
N2 - 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.
AB - 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.
KW - drug discovery
KW - lead optimization
KW - mitogen-activated protein kinases
KW - pancreatic cancer
KW - small molecule inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85116032165&partnerID=8YFLogxK
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U2 - 10.1021/acsmedchemlett.1c00376
DO - 10.1021/acsmedchemlett.1c00376
M3 - Article
C2 - 34676038
AN - SCOPUS:85116032165
SN - 1948-5875
VL - 12
SP - 1559
EP - 1567
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 10
ER -
