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 journalArticlepeer-review

2 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 languageEnglish
Article number2166039
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume38
Issue number1
DOIs
Publication statusPublished - 2023

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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