c-Met inhibitors are a class ofsmall molecules thatinhibit the enzymatic activity of thec-Mettyrosine kinase, thereceptor ofhepatocyte growth factor/scatter factor (HGF/SF). These inhibitors may have therapeutic application in the treatment of various types of cancers.[1]
Many c-Met inhibitors are currently[when?] inclinical trials.Crizotinib[2] andcabozantinib were the first to be approved by theU.S. FDA. Crizotinib received accelerated approval in 2011 for the treatment of patients with locally advanced or metastaticnon-small cell lung cancer, while cabozantinib was approved in 2012 for the treatment ofmedullary thyroid cancer[3] and it has also started clinical trials for the treatment of several other types of cancer.
c-Met stimulates cell scattering, invasion, protection fromapoptosis andangiogenesis.[4] c-Met is areceptor tyrosine kinase,[5] which can cause a wide variety of different cancers, such asrenal,gastric andsmall cell lung carcinomas,central nervous system tumours, as well as severalsarcomas[6] when its activity is dysregulated. Targeting theATP binding site of c-Met by smallmolecules inhibitors is one strategy for inhibition of the tyrosine kinase.[7]
Early in the 1980s MET was described as theprotein product of a transformingoncogene.[9][10]
Initial attempts to identify ATP-competitive c-Met inhibitors in 2002 led to the discovery ofK252a, astaurosporine-like inhibitor which blocks c-Met.[10][11]K252a was the first structure to be solved in complex with the unphosphorylated MET kinase domain. It forms twohydrogen bonds between the hinge and pyrralocarbazole subunit.[8]
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[9] and by adding a 3,5-dimethylpyrrole group, PHA-665752 was evolved[11] – a second-generation inhibitor with better potency and activity.[10]
Interest in this field has risen rapidly since 2007 and over 70 patent applications had been published in mid-2009.[10]
Intensive efforts have been exerted in thepharmaceutical industry following the acceptance of c-Met as a suitable target for cancer therapy. 20 crystal structures with and withoutligands have been published and in 2010 nearly a dozen small molecule c-Met inhibitors have been tested clinically.[12]
Receptor tyrosine kinases (RTKs) are a vital element in regulating manyintracellular signal transduction pathways.[13]Met tyrosine kinase is the receptor forhepatocyte growth factor (HGF), also known as scatter factor (SF). HGF is mostly expressed onepithelial cells andmesenchymal cells, for example smooth muscle cells andfibroblasts.[10][11] HGF is normally active in wound healing,liver regeneration,embryo and normalmammalian development,[10] organmorphogenesis.[11]
c-Met dysregulation can be due to overexpression, gene amplification,mutation, a ligand-dependent auto- or paracrine loop or an untimely activation of RTK.[10][13] All these factors affect the survival of cells, theirproliferation and motility. They also lead to cancers and resistance to therapies which aim to treat them.[13] Patients with aberrant c-Met activity usually have a poorprognosis, aggressive disease, increasedmetastasis and shortened survival.[10] This is why targeting the HGF/c-MET signalling pathway has been untaken as a treatment for cancer,[10][13] 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 byantibodies, peptideagonists,[4][10] decoy receptors and other biologic inhibitors[14]or small molecules inhibitors.[10]
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 ofsubstrates and downstream signalling.[10][17]
HGF is the natural high-affinity ligand for Met.[10][11][17] Its N-terminal region binds to Met and receptor dimerization as well asautophosphorylation of two tyrosines occur in theactivation loop (A-loop) in the kinase domain of Met.[10]
Phosphorylation occurs in tyrosines close to the C-terminus, creating a multi-functional docking site[10][18]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, alteredcytoskeletal 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.[10]
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 anacylthiourea group led to compounds with c-Met activity, e.g.quinoline.[10] 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 deephydrophobic pocket and so it enhances the potency of the compounds. Alternatives to the acyl thiourea linkage have been found, which have apyrimidone group, as in AM7.[19]
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 effectin 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.[20]
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).[20] There is however another type of small-molecule inhibitors, which does not fit into either of the two classes; anon-competitive ATP inhibitor that binds in a different way to the other two.[21]
The small molecule inhibitors vary in selectivity, are either very specific or have a broad selectivity. They are either ATP competitive or non-competitive.[12]
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[20]) and they all aim to mimic thepurine of ATP. BMS-777607 and PF-02341066 have a 2-amino-pyridine group, AMG-458 has aquinoline group and MK-2461 has a tricyclic aromatic group.[22]
Class I inhibitors have many different structures,[12] are relatively selective and have a U-shaped conformation[10] and binds to theactivation loop of c-Met.[12]
A series of triazolotriazines was discovered, which showed great promise as a c-MET inhibitors.Structure activity relationship (SAR) implies the necessity of anaryl group linked to thetriazine ring and an appropriate hydrogen bond acceptor (e.g. hydroxyl group) attached to the pendantbenzyl ring but it seems like thephenol acts as a hinge binder (with Met1160) and that thetriazine interacts with Tyr1230.[12]A number of similar analogues were found and assayed. Structurally similar series of c-Met inhibitors in which a phenolic hinge binding element was linked to an arylamino-triazolopyridazine or aryl-triazolothiapyridazine. One-atom linker was more efficient than a two-atom linker and that substitution at the benzylic position seemed to be tolerated. Compounds withheterocyclic hinge binding elements (quinoline,pyridine, azaindole) linked to fused, nitrogen-dense heteroaromatics (triazolopyridazines, triazolopyrazines and triazolotriazines) have been described.[12] See figure 4 for details.[12]
JNJ-38877605, which contains a difluoro methyl linker and abioavailable quinoline group, was undergoing clinical trials of Phase I for advanced and refractory solid tumours in 2010.[12] The trial was terminated early due to renal toxicity caused by metabolites of the agent.[23][24]
PF-04217903, an ATP-competitive and exceptionally selective compound, has an N-hydroxyethyl pyrazole group tethered to C-7 of thetriazolopyrazine. It was undergoing phase I clinical trials in 2010.[12][needs update]
The SAR of the unique kinase inhibitor scaffold with powerful c-Met inhibitory activity,MK-2461, has been explored.[25]The pyridine nitrogen is necessary for inhibition activity and central ring saturation reduced potency.[12] Planarity of the molecule has proven to be essential for maximum potency.[25] Cyclic ethers balance acceptable cell-based activities andpharmacokinetic 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 asulfonamide 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.[25] MK-2461 was undergoing phase I dose escalation trials in 2010.[12][needs update]
Class II inhibitors are usually not as selective as those of class I.[10]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.[12]
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 thethiourea 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 afluorine atom.[12]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 terminalamine interacts with theribose pocket (of ATP), the terminal 4-fluorophenyl group is oriented in a hydrophobic pocket and pyrrolotriazine plays the role of the hinge-binding group.[12]
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.[12]
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 intrinsichalf-life increased with higher mammals.[12]
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Tivantinib (ARQ197) is a selective, orally bioavailable,[17][21] clinically advanced low-molecular weight and well-tolerated c-MET inhibitor, which is currently[when?] in Phase III clinical trials innon-small cell lung cancer patients.[21] ARQ197 is a non-ATP competitive c-MET autophosphorylation inhibitor with a high selectivity for the unphosphorylated conformation of the kinase.[17][21] Tivantinib cuts off the interactions between the keycatalytic residues.[21]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.[21]
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.[17] 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.[10]
As of 2010[update] over a dozen Met pathway inhibitors, with varying kinase selectivity profiles ranging from highly selective to multi-targeted,[12] have been studied in the clinic and good progress has been achieved[17] (See table 1). (e.g.XL184(Cabozantinib),XL880,ARQ197 )[needs update]
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, includingchemo-,radio- orimmunotherapy as well as different Met pathway inhibitor, f.ex. in with HGF and Met biological antagonists or antibodies against HGF and MET.[17] Still, the risk of accumulated toxicity and interactions with other drugs remains.[10]
In 2011 PF-02341066 (now named crizotinib) was approved byUS FDA for somenon-small cell lung cancers.
In 2012 XL184/cabozantinib gained FDA approval to treatmedullary thyroid cancer, and in 2016 it gained FDA and EU approval to treat kidney cancer.
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Tepotinib, (MSC 2156119J),[26]
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has reported phase II clinical trial results on lung cancer.[27] Tepotinib was grantedbreakthrough therapy designation by the U.S.Food and Drug Administration (FDA) in September 2019.[28] It was grantedorphan drug designation in Japan in November 2019, and in Australia in September 2020.[29]