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An Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic Mechanisms

Departments of ¹ Cancer Biology, ² Pharmacokinetics, Dynamics, and Metabolism, ³ Biochemical Pharmacology, ⁴ Medicinal Chemistry, ⁵ Oncology, and ⁶ Molecular Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California

Requests for reprints: James G. Christensen, Department of Cancer Research, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, La Jolla, CA 92121. Phone: 858-638-6336; Fax: 858-526-4120; E-mail: james.christensen{at}pfizer.com.

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met–dependent proliferation, migration, or invasion of human tumor cells in vitro (IC₅₀ values, 5–20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met–dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers. [Cancer Res 2007;67(9):4408–17]

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