"Identification of Potential Kinase Inhibitors to Specifically Target Mkk4 for Skin Tumorigenesis"

Abstract

BJSTR. MS.ID.007627.MKK4, a Ser/Thr protein kinase, is one of the critical activators of MAP kinases in response to various mitogenic stimuli. MKK4 induces skin tumorigenesis through oncogenic activation of the ras gene. The MKK4 acts as the main component of JNK activation which directly induces the RAS signaling pathway. Overexpression of MKK4 is associated with the aggressiveness of various tumors including non-small cell lung, breast, prostate, stomach, and colon adenocarcinomas. Downstream signaling of MKK4 is important for the formation of tumors and hence acts as a potential drug target for cancer therapy. Interestingly, in the present study, it was found that Nilotinib and Dacomitinib bind to the catalytic pocket of MKK4 with the affinity of -9.47 and -9.00 kcal/mol respectively. It was observed that Nilotinib interacts with active site residues of MKK4 namely, Arg110, Lys187, Asp247, Ile108, and Leu236. In addition, it was also found that Dacomitinib interacts with active sites namely, Met181,