A Novel c-Met/TRK inhibitor 1D228 efficiently inhibits tumor growth by targeting angiogenesis and tumor cell proliferation.

Abstract

Abstract It has been reported that c-Met and TRK synergistically promote multiple tumour progression, and therefore blocking the cross-signalling pathway between them may inhibit the growth of multiple tumours. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited great anti-tumor activity by targeting TRK and c-Met. In the in vitro models, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the similar drug tepotinib. In the in vivo tumor models, 1D228 showed robust anti-tumor effect on gastric (TGI, 1D228-8 mg/kg/d: 94.8%; tepotinib 8mg/kg/d: 67.61%) and liver (TGI, 1D228-4 mg/kg/d: 93.4%; tepotinib 4mg/kg/d: 63.9%) tumor growth. Importantly, compared with the combination of larotrectinib and tepotinib, 1D228 monotherapy showed stronger antitumor activity and lower toxicity. Mechanistic studies showed that 1D228 can largely inhibit the phosphorylation of TRK and c-Met, thereby blocking downstream signaling pathways of TRK and c-Met. Interestingly, both kinases can be co-expressed at high levels in patients with gastric cancer. Cell cycle analysis found that 1D228 induced G0/G1 arrest by inhibiting cyclin D1. In addition, vascular endothelial cells also showed a pronounced response to 1D228 due to its expression of TRKB and c-Met. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. By histology analysis from the in vivo tumor tissues, we confirmed that 1D228 induced cancer cell apoptosis and inhibited tumor angiogenesis, leading to tumor growth retardation. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for gastric and hepatocellular carcinoma.