JNJ-38877605: a selective Met kinase inhibitor inducing regression of Met-driven tumor models.

Abstract

4837 The Met receptor tyrosine kinase and its ligand, hepatocytegrowth factor (HGF), have been implicated in the developmentand progression of several human cancers and have become compelling targets for developing anti-neoplastic agents. JNJ-38877605 was selected following extensive structure-based drug design and is a smallmolecule, ATP-competitive, inhibitor of the catalyticactivity of Met kinase (IC50 4 nM). JNJ-38877605 exhibited~600-fold selectivity (vs cFMS IC50 2.6μM ; the next most potently inhibited kinase) for Met compared with a panel of ~250 diversetyrosine and serine-threonine kinases. In cellular studies,JNJ-38877605 was found to potently inhibit HGF-stimulated and constitutively activatedMet phosphorylation, and HGF and Met-driven phenotypessuch as cell motility,invasion, cell proliferation (exclusively in Met amplified cells), and/or morphology of a variety of tumor cells. JNJ-38877605 inhibits all known HGF-stimulated or constitutivelyactivated downstream mediators of the Met kinase pathway. JNJ-38877605 showed excellent oral bioavailability approaching 100% in all species examined. In addition, a single dose of JNJ-38877605 was observed toinhibit Met phosphorylation in tumor xenografts for up to16 h following a single oral dose. Inhibition of Met phosphorylation was associated withdose-dependent tumor growth inhibition using a range of oral dosing regimens. JNJ-38877605 was observed to induce significant tumor regression in large, well established MET gene amplified gastric cancer models and in Met pathway- activated (autocrine or paracrine) models.The highly favourable preclinical properties of JNJ-38877605 together with the extremely clean GLP toxicity profile of this compound has resulted in the selection of this potent and uniquely selective Met inhibitor for clinical evaluation.