Abstract 1029: Identification of novel MEK1 inhibitors by computer docking and virtual screening

Abstract

Abstract The mitogen-activated protein kinase kinase 1 (MEK1) signaling pathway is a major component of the RAS/RAF/MEK/ERK signaling axis that regulates tumorigenesis and cancer cell proliferation. MEK1 is frequently activated in various cancers, especially in tumors that have mutations in the KRAS and BRAF oncogenes. Therefore MEK1 is an important cancer therapy target and the discovery of novel MEK1 inhibitors is of great interest. We used the MEK1 protein crystal structure and supercomputer screening of chemical libraries combined with simulation modeling and in vitro, ex vivo and in vivo assays to identify novel inhibitors of MEK1. Herein, we report the discovery of threee novel MEK1 inhibitors, herein referred to as Compound #7, #9 and #12. All three were highly effective to suppress MEK1 activity in HCT116 and HCT15 colorectal cancer cells. Based on in vitro and ex vivo data, these compounds inhibited MEK1 activity and phosphorylation of ERK1/2 in a dose-dependent manner and were twice as effective than the known MEK1 inhibitor, U0126. The compounds completely inhibited anchorage-independent cell growth and proliferation of colon cancer cells. Overall these results suggest that these novel MEK1 inhibitors might be used for chemotherapy; and computer modeling and simulation could be very useful for finding additional MEK1 or other inhibitors for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1029. doi:10.1158/1538-7445.AM2011-1029