In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer

Chao Di Chang; Min Wu Chao; Hsueh Yun Lee; Yi Ting Liu; Huang Ju Tu; Ssu Ting Lien; Tony Eight Lin; Tzu Ying Sung; Shih Chung Yen; Sing Han Huang; Kai Cheng Hsu; Shiow Lin Pan

doi:10.1080/14756366.2023.2166039

In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer

Chao Di Chang, Min Wu Chao, Hsueh Yun Lee, Yi Ting Liu, Huang Ju Tu, Ssu Ting Lien, Tony Eight Lin, Tzu Ying Sung, Shih Chung Yen, Sing Han Huang, Kai Cheng Hsu, Shiow Lin Pan

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC₅₀ 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

Original language	English
Article number	2166039
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	38
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2023.2166039
Publication status	Published - 2023

Keywords

JNK signalling pathway
kinase inhibitor
MAP4K4
pancreatic cancer
structure-based virtual screening

ASJC Scopus subject areas

Pharmacology
Drug Discovery

UN SDGs

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

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10.1080/14756366.2023.2166039

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Chang, C. D., Chao, M. W., Lee, H. Y., Liu, Y. T., Tu, H. J., Lien, S. T., Lin, T. E., Sung, T. Y., Yen, S. C., Huang, S. H., Hsu, K. C., & Pan, S. L. (2023). In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer. Journal of Enzyme Inhibition and Medicinal Chemistry, 38(1), Article 2166039. https://doi.org/10.1080/14756366.2023.2166039

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title = "In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer",

abstract = "Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.",

keywords = "JNK signalling pathway, kinase inhibitor, MAP4K4, pancreatic cancer, structure-based virtual screening",

author = "Chang, {Chao Di} and Chao, {Min Wu} and Lee, {Hsueh Yun} and Liu, {Yi Ting} and Tu, {Huang Ju} and Lien, {Ssu Ting} and Lin, {Tony Eight} and Sung, {Tzu Ying} and Yen, {Shih Chung} and Huang, {Sing Han} and Hsu, {Kai Cheng} and Pan, {Shiow Lin}",

note = "Funding Information: We gratefully acknowledge the support from the Ministry of Science and Technology (MOST 111-2320-B-038-042-MY3 and MOST 111-2622-B-038-009). This research was also partially supported by the Biomedical Translation Research Center, Academia Sinica (Grant No. AS-BRPT-112-11) and {"}TMU Research Center of Cancer Translational Medicine{"} from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. We also acknowledge Graphen Inc. for the RNA-seq data analysis of pancreatic cancer. Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.",

year = "2023",

doi = "10.1080/14756366.2023.2166039",

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T1 - In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer

AU - Chang, Chao Di

AU - Chao, Min Wu

AU - Lee, Hsueh Yun

AU - Liu, Yi Ting

AU - Tu, Huang Ju

AU - Lien, Ssu Ting

AU - Lin, Tony Eight

AU - Sung, Tzu Ying

AU - Yen, Shih Chung

AU - Huang, Sing Han

AU - Hsu, Kai Cheng

AU - Pan, Shiow Lin

N1 - Funding Information: We gratefully acknowledge the support from the Ministry of Science and Technology (MOST 111-2320-B-038-042-MY3 and MOST 111-2622-B-038-009). This research was also partially supported by the Biomedical Translation Research Center, Academia Sinica (Grant No. AS-BRPT-112-11) and "TMU Research Center of Cancer Translational Medicine" from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. We also acknowledge Graphen Inc. for the RNA-seq data analysis of pancreatic cancer. Publisher Copyright: © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

PY - 2023

Y1 - 2023

N2 - Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

AB - Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

KW - JNK signalling pathway

KW - kinase inhibitor

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KW - structure-based virtual screening

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In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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