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

doi:10.1021/acsmedchemlett.1c00376

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 journal › Article › peer-review

6 Scopus citations

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 language	English (US)
Pages (from-to)	1559-1567
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	12
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00376
State	Published - Oct 14 2021

Funding

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.

Keywords

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

ASJC Scopus subject areas

Drug Discovery
Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsmedchemlett.1c00376

Cite this

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

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.",

keywords = "drug discovery, lead optimization, mitogen-activated protein kinases, pancreatic cancer, small molecule inhibitors",

author = "Kwong, {Ada J.} and Pham, {Thao N.D.} and Oelschlager, {Hannah E.} and Munshi, {Hidayatullah G.} and Scheidt, {Karl A.}",

note = "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: {\textcopyright} 2021 American Chemical Society.",

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doi = "10.1021/acsmedchemlett.1c00376",

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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.

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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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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