Altiratinib, a novel c-MET/TIE-2/VEGFR inhibitor, was able to effectively reduce tumor burden in vivo and block c-MET signaling, cell growth and migration. Altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases. It is currently in Phase 1 clinical development for the treatment of solid tumors.

JNJ-38877605 is an orally available, small molecule inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. c-Met inhibitor JNJ-38877605 selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. JNJ-38877605 was in Phase I clinical trials. Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.

Savolitinib (AZD6094, HMPL-504) has been demonstrated to inhibit the growth of tumors in a series of preclinical disease models, selectively for those tumors with aberrant c-Met signaling. Phase I dose escalation studies were initiated in Australia and China in 2012 and 2013 respectively. Savolitinib has demonstrated good safety and tolerability and favorable pharmacokinetic properties in late stage cancer patients, and has shown encouraging anti-tumor activity in several tumor-types, in particular for metastatic Papillary Renal Cell Cancer (PRCC). Phase II, study designed to evaluate the efficacy and safety of savolitinib in patients with locally advanced or metastatic PRCC. Approximately 20 centers in the United States, Canada, and Europe will participate in the study. The primary objective of this study is to assess the anti-tumor activity in patients with PRCC as measured by overall response rate according to Response Evaluation Criteria in Solid Tumours (“RECIST”). The secondary objectives for this study are to: assess the progression free survival and duration of response in patients with PRCC according to RECIST; assess the safety and tolerability in the treatment of patients with PRCC; characterize the pharmacokinetics and pharmacodynamics of savolitinib and metabolites following administration to steady state after multiple dosing when given orally.

SGX523 is a selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase. SGX523 was able to inhibit HGF-induced cell migration and cell scatter. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers. The clinical development of SGX523, however, was discontinued at Phase I due to renal toxicity manifested by an early rise of serum blood urea nitrogen and creatinine.

MK-8033 is a dual c-Met/Ron inhibitor, which is under investigation by Merck for the treatment of cancer.

The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. MK-2461 is a novel ATP-competitive multitargeted inhibitor of activated c-Met, was synthesized by Merck and was investigated in phase I of clinical trial for the potential treatment of patients with advanced solid tumors.

Amgen was developing AMG-208, a small molecule inhibitor of c-Met, for the treatment of cancer. AMG-208 shows the potent inhibition of kinase c-Met activity with IC50 of 9 nM in a cell-free assay. Besides, AMG-208 treatment also leads to the inhibition of HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM. AMG-208 showed evidence of antitumor activity, particularly in prostate cancer. On December 1, 2014 Amgen completed a phase I trial in solid tumours.

BMS 777607 is a substituted 2-aminopyridine shown to inhibit the RON and cMet receptor tyrosine kinases, for the treatment of solid tumors. BMS 777607 demonstrated ligand stimulated and constitutive Met phosphorylation, and inhibition of tumor cell proliferation, in preclinical studies. Preclinical data indicated that BMS 777607 inhibited RON, blocking the conversion of micrometastases to overt metastases by boosting antitumor immunity. Bristol-Myers Squibb conducted a phase I/II trial of BMS 777607 for the treatment of advanced solid tumors in Australia. As at December 2016, no recent reports of development had been identified for preclinical development in Cancer in the USA.

AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the cell surface enzyme called c-Met, which, when dysregulated, stimulates cancer cell scattering, invasion and protection from apoptosis. AMG 337, currently in Phase 2 development for the treatment of gastric and esophageal adenocarcinoma. In addition, recently was shown, that AMG 337 a promising and novel therapeutic strategy for targeting hepatocellular carcinomas with a dependence on HGF/MET signaling.