Background: c-Met is a proto-oncogene that encodes the protein Met with intrinsic tyrosine kinase activity. Aberrant Met kinase activity triggers a series of unwarranted phosphorylation events and signalling processes that ultimately lead to the development of cancer. Alteration of the Met kinase signalling cascade represents an attractive approach aimed at blocking invasion and metastasis of cancer cells. Herein, we describe the biological and pharmacokinetic properties of representative molecules from a series of novel and small molecule inhibitors with scope to be further developed as clinical candidates for cancers mediated by dysregulated Met kinase activity. Methods: Met Kinase activity of test compounds was determined using an HTRF® KinEASE assay kit (Cisbio, Bedford, MA) with modifications. Met-dependent anti-proliferative effect was determined in MKN-45 cells. Inhibition of constitutive Met kinase phosphorylation in MKN-45 and NCI-H441 cells was measured in an ELISA assay. Subsequently, effect of the compounds on Akt phosphorylation, a downstream marker in the Met signalling cascade, was determined. Metabolic stability of the compounds was evaluated in microsomes obtained from mouse, rat, dog, monkey, and human. Results: Among the compounds evaluated, RP1269 and RP1316 demonstrated remarkable potency against the purified Met kinase enzyme (20.17 & 40.5 nM) as well as in an MKN-45 cell proliferation assay (18.0 & 2.3 nM). In addition, the compounds caused a significant reduction in constitutive Met kinase phosphorylation in MKN-45 (11.5 & 33.3 nM) and NCI-H441 (2.2 & 4.1 nM) cells. As a consequence, Akt phosphorylation was inhibited at half-maximally in MKN-45 and NCI-H441 cells at <100 nM and <50 nM respectively. Further, the compounds exhibited a favourable ADME profile across the species studied. Conclusions: Our findings demonstrate that RP1269 and RP1316 are potent Met kinase inhibitors with efficacy values comparable to existing Met kinase inhibitors in development. On lines with selective inhibitors, the compounds display anti-proliferative effect only in cells with amplification of the Met kinase gene. The compounds are currently being tested for efficacy and target inhibition in various xenograft models. Clinical candidate shall be nominated by 2012.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1789. doi:1538-7445.AM2012-1789