Harnessing the Therapeutic Potential of TAS-115: A Dual c-Met and VEGFRs Inhibitor with Enhanced Safety Profile

The c-Met receptor tyrosine kinase is implicated in various cancers due to its role in promoting malignant phenotypes and its association with poor outcomes. VEGF/VEGFR inhibition has become a standard treatment for some cancers, and recent findings indicate a synergistic effect between RTKs in promoting cancer progression. Dual inhibition of c-Met and VEGFRs is a promising therapeutic strategy, and several compounds targeting both have been clinically evaluated. However, clinical success has been limited due to issues with selectivity and toxicity from VEGFR inhibition, which affects tolerability and dosing.

To overcome these challenges, TAS-115 was developed as a novel dual inhibitor of c-Met and VEGFRs. In vitro assays showed TAS-115 to be a potent ATP-competitive inhibitor of both targets, with an IC50 around 10 nM, surpassing known inhibitors like crizotinib, foretinib, and sunitinib. TAS-115 effectively inhibited kinase phosphorylation and cell growth dependent on HGF/c-Met or VEGF, with a significant selectivity advantage over other inhibitors. This selectivity was further validated across 40 cell lines, correlating IC50 values with HGF and c-Met mRNA expression.

In vivo studies demonstrated TAS-115's potent anti-tumor activity in both c-Met positive and negative xenografts, leading to complete tumor eradication and the disruption of c-Met and VEGFR2 signaling pathways. The effective doses ranged from 4 to 30 mg/kg across 12 xenograft models. Notably, TAS-115 showed excellent tolerability with no animal deaths even at exposures 28 times higher than the ED50 values, contrasting favorably with other VEGFR inhibitors.

The study concludes that TAS-115 is a highly potent and selective c-Met and VEGFRs dual inhibitor with a safer profile, suggesting its potential as a therapeutic agent for human cancers. The research was presented at the 102nd Annual Meeting of the American Association for Cancer Research and published in Cancer Research.