Abstract 3606: CH5126766 is a novel allosteric inhibitor of MEK that prevents its phosphorylation by RAF

Abstract

Abstract Tumors with mutant BRAF or RAS are often dependent on the ERK signaling pathway. MEK and RAF inhibitors have significant antitumor activity in patients with BRAF mutant melanoma, but, thus far, MEK inhibitors have little activity in patients whose tumors contain mutant RAS. The effectiveness of the drugs seems to require near complete inhibition of ERK signaling. MEK inhibition has been shown to lead to relief of feedback inhibition of RAF and induction of MEK phosphorylation. It is possible that this induction attenuates inhibition of the pathway and reduces clinical activity. We have now isolated and characterized an allosteric inhibitor of MEK, CH5126766, with novel properties that prevent its induction of MEK phosphorylation. CH5126766 causes MEK to bind to RAF tightly and in a conformation in which it cannot be phosphorylated. MEK in this complex has low kinase activity and may act as a dominant negative inhibitor when bound to RAF. Compared to the MEK inhibitor PD0325901, CH5126766 inhibits ERK signaling output in cells more potently and has greater antitumor activity in the KRAS mutant colorectal cancer HCT116 grown as a murine xenograft. MEK inhibitors such as CH5126766 will inhibit feedback induction of MEK phosphorylation and this may allow more complete pathway inhibition and result in greater antitumor activity. 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 3606. doi:10.1158/1538-7445.AM2011-3606