C-Met inhibitor

Initial attempts to identify ATP-competitive c-Met inhibitors in 2002 led to the discovery of K252a, a staurosporine-like inhibitor which blocks c-Met. Later, series of more selective c-Met inhibitors were designed, where an indolin-2-one core (encircled in figure 1) was present in several kinase inhibitors. SU-11274 was evolved by substitution at the 5-position of the indolinone and by adding a 3,5-dimethyl pyrrole group, PHA-665752 was evolved – a second-generation inhibitor with better potency and activity. Interest in this field has risen rapidly since 2007 and over 70 patent applications had been published in mid-2009. Intensive efforts have been exerted in the pharmaceutical industry following the acceptance of c-Met as a suitable target for cancer therapy. 20 crystal structures with and without ligands have been published and in 2010 nearly a dozen small molecule c-Met inhibitors have been tested clinically.{{Citation == Introduction ==

Receptor tyrosine kinases (RTKs) are a vital element in regulating many intracellular signal transduction pathways.{{Citation Met tyrosine kinase is the receptor for hepatocyte growth factor (HGF), also known as scatter factor (SF). HGF is mostly expressed on epithelial cells and mesenchymal cells, for example smooth muscle cells and fibroblasts. HGF is normally active in wound healing, liver regeneration, embryo and normal mammalian development, organ morphogenesis. c-Met dysregulation can be due to overexpression, gene amplification, mutation, a ligand-dependent auto- or paracrine loop or an untimely activation of RTK. All these factors affect the survival of cells, their proliferation and motility. They also lead to cancers and resistance to therapies which aim to treat them. Patients with aberrant c-Met activity usually have a poor prognosis, aggressive disease, increased metastasis and shortened survival. This is why targeting the HGF/c-MET signalling pathway has been untaken as a treatment for cancer, and several different therapeutic approaches are being clinically tested. A variety of approaches have been used to target c-Met, each focusing on one of the serial steps that regulate c-Met activation by antibodies, peptide agonists, decoy receptors and other biologic inhibitors{{Citation or small molecules inhibitors. == Structure and function ==

), Sema domain (Semaphorin-like), PSI (Plexins, Semaphorins, Integrins), IPT domain (Immunoglobulin-like, Plexins, Transcription factors) and PTK (Protein Tyrosine Kinase).{{Citation , B: Hydrophobic sub-pocket C: Central hydrophobic region, D: Hinge region, E: Hydrophobic sub-pocket.{{Citation The c-Met RTK subfamily is different in structure to many other RTK families: The mature form has an extracellular α-chain (50kDa) and a transmembrane β-chain (140kDa) that are linked together by a disulfide bond. The beta chain contains the intracellular tyrosine kinase domain and a tail on the C-terminal which is vital for the docking of substrates and downstream signalling. {{Citation HGF is the natural high-affinity ligand for Met. Its N-terminal region binds to Met and receptor dimerization as well as autophosphorylation of two tyrosines occur in the activation loop (A-loop) in the kinase domain of Met. Phosphorylation occurs in tyrosines close to the C-terminus, creating a multi-functional docking site{{Citation which recruits adaptor proteins and leads to downstream signalling. 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. == Development ==

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. The small molecule inhibitors vary in selectivity, are either very specific or have a broad selectivity. They are either ATP competitive or non-competitive. == ATP-competitive small molecule c-Met inhibitors ==

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 PF-04217903, an ATP-competitive and exceptionally selective compound, has an N-hydroxyethyl pyrazole group tethered to C-7 of the triazolopyrazine. It was undergoing phase I clinical trials in 2010. The pyridine nitrogen is necessary for inhibition activity and central ring saturation reduced potency. Planarity of the molecule has proven to be essential for maximum potency. Cyclic ethers balance acceptable cell-based activities and pharmacokinetic characteristics. The following elements are thought to be key in the optimization process: 1) Aryl groups at the 7-position, as if to maximize hydrophobic packing and planarity, 2) The tight SAR upon the addition of a sulfonamide group and 3) The relatively flat SAR of solvent-exposed groups. Often, oncogenic mutations of c-Met cause a resistance to small molecule inhibitors. An MK-2461 analog was therefore tested against a variety of c-Met mutants but proved to be no less potent against them. This gives the molecule a big advantage as a treatment for tumours caused by c-Met dysregulation. MK-2461 was undergoing phase I dose escalation trials in 2010. Class II Class II inhibitors are usually not as selective as those of class I. Urea groups are also a common feature of class II inhibitors, either in cyclic or acyclic forms. Class II of inhibitors contains a number of different molecules, a common scaffold of which can be seen in figure 4. Structure-activity relationship of Class II inhibitors Series of quinoline c-Met inhibitors with an acylthiourea linkage have been explored. Multiple series of analogs have been found with alternative hinge binding groups (e.g. replacement of the quinoline group), replacement of the thiourea linkage (e.g. malonamide, oxalamide, pyrazolones) and constraining of the acyclic acylthiourea structure fragment with various aromatic heterocycles. Further refinement included the blocking of the p-position of the pendant phenyl ring with a fluorine atom. Example of interactions between c-Met and a small molecules (marked in a red circle) of class II are as follows: The scaffold of c-Met lodges into the ATP pocket by three key hydrogen bonds, the terminal amine interacts with the ribose 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 (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. 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. ==See also==