Abstract

Activation of the Ras/Raf/MEK/MAP kinase pathway is implicated in uncontrolled cell proliferation and tumor growth¾ Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic, and 30% of lung cancers; B-Raf mutations have been identified in more than 60% of malignantmelanomas and from 40-70% of papillary thyroid cancers ¾ MEK, a dual specific kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. ¾ ARRY-162, a novel ATP-uncompetitive inhibitor of MEK1/2, has nanomolar activity against purified MEK enzyme (IC50= 12 nM) and inhibits both basal and induced levels of ERK phosphorylation in numerous cancer cell lines with IC50s as low as 5 nM¾ ARRY-162 is especially potent at inhibiting the cell proliferation of mutant B-Raf and Ras celllines such as HT29, Malme-3M, SK-MEL-2, COLO 205, SK-MEL-28 and A375 (IC50s from 30-250 nM) ¾ In vivo, ARRY-162 has demonstrated efficacy in several xenograft tumor models in mice,including HT29, BxPC3, MIA PaCa2, A549, LoVo, Calu6, DU145 and COLO 205 ¾ ARRY-162 demonstrates good physical chemical characteristics, low clearance, medium-tohigh Caco-2 permeability and minimal predicted drug-drug interactions