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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2166039. doi: 10.1080/14756366.2023.2166039.

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; MAP4K4; kinase inhibitor; pancreatic cancer; structure-based virtual screening.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Computer Simulation
  • Gemcitabine / chemistry
  • Gemcitabine / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Pancreatic Neoplasms* / enzymology
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Serine-Threonine Kinases* / antagonists & inhibitors

Substances

  • Gemcitabine
  • Intracellular Signaling Peptides and Proteins
  • MAP4K4 protein, human
  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Antineoplastic Agents

Grants and funding

This research was supported by 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.