pocket (of atp), the terminal 4-fluorophenyl group is oriented in a hydrophobic pocket and pyrrolotriazine plays the role of the hinge-binding group. examples of class ii inhibitors in phase ii clinical trials, gsk 1363089 (xl880, foretinib) was well tolerated. it led to slight regressions or stable disease in patients with papillary renal carcinoma and poorly differentiated gastric cancer. amg 458 is a potent small molecule c-met inhibitor which proved to have more than a 100-fold selectivity for c-met across a panel of 55 kinases. also, amg 458 was 100% bioavailable across species and the intrinsic half-life increased with higher mammals. atp non-competitive small molecule c-met inhibitors tivantinib tivantinib (arq197), a c-met inhibitor tivantinib (arq197) is a selective, orally bioavailable, clinically advanced low-molecular weight and well-tolerated c-met inhibitor, which is currently in phase iii clinical trials in non-small cell lung cancer patients. arq197 is a non-atp competitive c-met autophosphorylation inhibitor with a high selectivity for the unphosphorylated conformation of the kinase. tivantinib cuts off the interactions between the key catalytic residues. the structure of tivantinib in complex with the c-met kinase domain shows that the inhibitor binds a conformation that is distinct from published kinase structures. tivantinib strongly inhibits c-met autoactivation by selectively targeting the inactive form of the kinase between the n- and c- lobes and occupies the atp binding site. clinical trials and regulatory approvals status as of 2010 since the discovery of met and hgf, much research interest has focused on their roles in cancer. the met pathway is one of the most frequently dysregulated pathways in human cancer. increased understanding of the binding modes and structural design brings us closer to the use of other protein interactions and binding pockets, creating inhibitors with alternative structures and optimized profiles. table 1. examples of small molecule c-met inhibitors in clinical trials (2010).snd: structure not disclosed; ron: recepteur d'origine nantais alk: anaplastic lymphoma kinase; vegfr2: vascular-endothelial growth factor receptor 2; mit: microphthalmia transcription factor tumors; pdac: pancreatic ductal adenocarcinoma; nsclc: non-small cell lung carcinoma; hcc: hepatocellular carcinoma; mtc: medullary thyroid carcinoma; gbm: glioblastoma; rcc: renal cell carcinoma; hnscc: head and neck squamous cell cainoma; ind: investigational new drug. as of 2010 over a dozen met pathway inhibitors, with varying kinase selectivity profiles ranging from highly selective to multi-targeted, have been studied in the clinic and good progress has been achieved (see table 1). (e.g. xl184(cabozantinib), xl880, arq197 ) the use of c-met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. met pathway inhibitors might be used in combination with other treatments, including chemo-, radio- or immunotherapy as well as different met pathway inhibitor, f.ex. in with hgf and met biological antagonists or antibodies against hgf and met. still, the risk of accumulated toxicity and interactions with other drugs remains. since 2010 in 2011 pf-02341066 (now named crizotinib) was approved by us fda for some non-small cell lung cancers. in 2012 xl184/cabozantinib gained fda approval to treat medullary thyroid cancer, and in 2016 it gained fda and eu approval to treat kidney cancer. research on other inhibitors tepotinib, (msc 2156119j), has reported phase ii clinical trial results on lung cancer. tepotinib was granted breakthrough therapy designation by the u.s. food and drug administration (fda) in september 2019. it was granted orphan drug designation in japan in november 2019, and in australia in september 2020.