definiens: shall mean a compound of con lirmed structure that meets the rollowing criteria : M£K : lesn : S I 0 ~M ( b ) Initial Qualified Lead Compound criteria A compound of conlinncd structure that meets all of tht : following in vitru parameters : MF : K : Ie,,:s I flM Functional Activity : Cdl Reversion IC50 < 1 0 ~M ; MTT Cell Proliferati on ICso ~ 10!J.\1 Kinase SeLeclivity : > ' lO - foJd Vt : fSUS a panel of protein kinascs ( including but not restricted to PKA, PKC, EGF receptor, insulin rcceptor, p38 kinase, VEGF receptor 2, FGf receptor, cdk2, and Src ) ( c ) Optimizalion goal The goal of the Research Program shall be to produce compounds which mc ~ t as closely as possible the following in vitro and in vivo parameters : MEK : lesn : S 50 nM Functional Activity : Cell Reversion IC50 .::::500 nYt ; MTT Cell Proliferation lC50 ~500 nM Killase Selectivity : 2::50 - fold against a panel of protein kinases ( see Qualified Lead Compound ) General Selectivity : ? : lOO - fold selective versus a panel of phanrmcological targets, including without hmitation GPCRs, enzymes, and ion channels ( Ccrep Screen ) Afoler : lIIar WeiKht :, : S600 Daitons /,ogl ): O,:SlogP:::5.5, as detennincd by AlogP, cLogP, or cx.perimcntal1ogP Aqueous Soluhility ( Cf : v.l'lalline, free base or salt form ): 2 : : 1 OO!-lgim L Caco-2 permeabili1y : 2::100 nm / s CYP450 inhibition : ICsu2:1 0, uM against I A2 . 2C9, 2C19, 2D6, and 3A4 isocnzymcs JlF : IIC : IC,,2 : IO, tM JlNA ( human hepatocyte assay ): rC5u2::50}lM III parent and CYP450 transfectcd celiltnes GellOloxiciry : < 2 - fold increase in revertants in Ames assay Rate of liver microsome melaholism ( mouse / human ): SO.2 nmollmin / mg protein Oral Hioavailabi / iry ( I rodent, 1 non - rodent species ): ? : .20 % In Vivo efficacy : Errieacy equivalenT or superior to thai observGd with CI - J 040 in 3 solid tumor I xenograft models in mice