The signaling is mediated by Ras/Mapk, PI3K/Akt, c-Src and STAT3/5 and include cell proliferation, reduced apoptosis, altered cytoskeletal function and more. The kinase domain usually consists of a bi-lobed structure, where the lobes are connected with a hinge region, adjacent to the very conserved ATP binding site. Using information from the co-crystal structure of PHA-66752 and c-Met, the selective inhibitor PF-2341066 was designed. It was undergoing Phase I/II clinical trials in 2010. Changing a series of 4-phenoxyquinoline compounds with an acyl thiourea group led to compounds with c-Met activity, e.g. quinoline. This was a key step in the progress of c-Met inhibitor development in that the acyl binding gives the terminal aryl group the ability to penetrate a deep hydrophobic pocket and so it enhances the potency of the compounds. Alternatives to the acyl thiourea linkage have been found, which have a pyrimidone group, as in AM7. AM7 and SU11274 offered the first proof that relatively selective c-Met inhibitors could be identified and that the inhibition leads to an anti-tumour effect in vivo. When the co-crystal structures of AM7 and SU11274 with c-Met were compared, they were found to be different: SU-11274 binds adjacent to the hinge region with a U-shaped conformation; but AM7 binds to c-Met in an extended conformation which spans the area from the hinge region to the C-helix. It then binds in a hydrophobic pocket. c-Met assumes an inactive, unphosphorylated conformation with AM7, which can bind to both phosphorylated and unphosphorylated conformations of the kinase. Due to these two different types of binding, small molecule Met inhibitors have been divided into two classes; class I (SU-11274-like) and class II (AM7-like). There is however another type of small-molecule inhibitors, which does not fit into either of the two classes; a non-competitive ATP inhibitor that binds in a different way to the other two. The small molecule inhibitors vary in selectivity, are either very specific or have a broad selectivity. They are either ATP competitive or non-competitive. Even though the two classes are structurally different, they do share some properties: They both bind at the kinase hinge region (although they occupy different parts of the c-Met active site) and they all aim to mimic the purine of ATP.