DESIGNING NOVEL MEK1 INHIBITORS AS ANTICANCER AGENTS

Life Sciences-Biotechnology

Abstract

MEK1 is a key player of Ras-Raf-MEK-ERK pathway, a widely studied pathway in cancer biology. MEK1 inhibitors therefore are promising agents for cancer treatment. Recently, the combination of MEK1 inhibitors and PPARgamma agonists are emerging as effective anticancer therapy. Here, we studied the designing of novel allosteric-MEK1 inhibitors using common feature pharmacophore protocol of DS3.5. The best hypothesis, Hypo1 was selected based on rank and max-fit value and validated with Güner-Henry scoring method. The validated model was used as template to screen an in-house database in order to retrieve potential hits. Top ranking hits were subjected to docking to analyze their interactions with MEK1. Based on the interaction energy and binding mode, 115 compounds were selected for in vitro assay against MIA PACA-2 and PC-3 cells. Five compounds show percent inhibition of 45.8-52.2% against MIA PACA-2 cells. Compounds were further tested for inhibition of p-ERK expression, the immediate downstream kinase of MEK1. Compound 72 shows 35% inhibition of p-ERK expression.