Abstract C212: Pharmacological and pharmacokinetc characterization of RP1040, a novel and potent c-Met tyrosine kinase inhibitor

Abstract

Abstract Background: Receptor tyrosine kinases (RTK) represent a class of high affinity cell surface receptors that play a critical role in the development and progression of several types of cancers. Among the receptor tyrosine kinases, c-Met mediates diverse cellular responses critical for tumor progression, growth, and survival. Alteration of the c-Met signalling cascade represents an attractive approach aimed at blocking invasion and metastasis of cancer cells. The objective of this study was to investigate the pharmacological and pharmacokinetic properties of RP1040, a novel small-molecule inhibitor of c-Met kinase. Methods: c-Met Kinase activity of RP1040 was determined using using an HTScan® recombinant human Met Kinase Assay Kit (Cell Signaling Technology, Beverly, MA) with modifications. Viability assay (MTT) was conducted to determine the growth inhibitory effect of the compound on the high c-Met expressing sk-LMS-1 cell line. Metabolic stability of the compound was evaluated in microsomes obtained from mouse, rat, dog, monkey, and human. Pharmacokinetic behaviour of RP1040 in plasma after single dose oral administration or IV injection was determined in male Wistar rats. Results: RP1040 demonstrated remarkable potency against the purified Met kinase by inhibiting enzyme activity at low nanomolar concentrations (IC50 = 1.3 nM). In addition, the compound caused a significant reduction in viability of sk-LMS-1 cells stimulated with 100 ng/ml HGF (IC50 = 0.03 nM). Pharmacokinetic studies indicated good oral absorption of RP1040 with plasma concentrations above 100 nM up to 24 h post administration. The compound had an elimination half-life of 8.95 hr with a clearance value of 4.21 ml/min/kg indicating a propensity to act as a long acting drug in this class. Further, RP1040 was metabolically stable across the species studied. Conclusions: Our results demonstrate that RP1040 is a potent c-Met kinase inhibitor with a favourable pharmacokinetic profile and superior IC50 values compared to existing c-Met kinase inhibitors in development. RP1040 is currently being tested for in vitro and in vivo efficacy across various cancer cell lines and xenograft models besides selectivity against other receptor tyrosine kinases. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C212.