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 (IC 50 120.7 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.

Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases

“…The compound F389-0746 has been identified as a potential MAP4K4 inhibitor that could inhibit its activity with an IC50 value of 120.7 nM. Compared to gemcitabine, F389-0746 showed better anticancer activity, including tumor growth inhibition in a xenograft pancreatic model [ 84 ]. Overall, the role of MAP4K4 in pancreatic malignancy is crucial and might be used for future therapeutic targets.…”