c-Met inhibitor

[4] c-Met is a receptor tyrosine kinase,[5] which can cause a wide variety of different cancers, such as renal, gastric and small cell lung carcinomas, central nervous system tumours, as well as several sarcomas[6] when its activity is dysregulated.

Targeting the ATP binding site of c-Met by small molecules inhibitors is one strategy for inhibition of the tyrosine kinase.

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.

[12] Receptor tyrosine kinases (RTKs) are a vital element in regulating many intracellular signal transduction pathways.

[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.

[13] Patients with aberrant c-Met activity usually have a poor prognosis, aggressive disease, increased metastasis and shortened survival.

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.

[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, 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.

[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 deep hydrophobic pocket and so it enhances the potency of the compounds.

[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 effect in vivo.

[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 the purine of ATP.

Structurally similar series of c-Met inhibitors in which a phenolic hinge binding element was linked to an arylamino-triazolopyridazine or aryl-triazolothiapyridazine.

Compounds with heterocyclic hinge binding elements (quinoline, pyridine, azaindole) linked to fused, nitrogen-dense heteroaromatics (triazolopyridazines, triazolopyrazines and triazolotriazines) have been described.

[12] JNJ-38877605, which contains a difluoro methyl linker and a bioavailable quinoline group, was undergoing clinical trials of Phase I for advanced and refractory solid tumours in 2010.

It led to slight regressions or stable disease in patients with papillary renal carcinoma and poorly differentiated gastric cancer.

[12] Tivantinib (ARQ197) is a selective, orally bioavailable,[17][21] clinically advanced low-molecular weight and well-tolerated c-MET inhibitor, which is currently[when?]

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.

(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.

Figure 3. K252a, the first small molecule Met inhibitor to be solved in complex with the unphosphorylated Met kinase domain. Two key hydrogen bonds form between the hinge of Met and the pyrrolocarbazole. [ 8 ]
Figure 1. SU11274, a first generation c-Met inhibitor (indolin-2-one core in red circle).
Figure 2. PHA665752, a second-generation c-Met inhibitor.
Figure 4. Schematic structure of some Met inhibitory possibilities: Antibodies and antagonists (such as NK4) bind to the extracellular domain. Met fragments of the extracellular domain can also bind to HGF and act as a decoy Met. Small molecule inhibitors bind to the intracellular Met kinase. Functional domains of Met: P encircled (Phosphate group), S-S ( disulfide bond ), Sema domain (Semaphorin-like), PSI (Plexins, Semaphorins, Integrins), IPT domain (Immunoglobulin-like, Plexins, Transcription factors) and PTK (Protein Tyrosine Kinase). [ 15 ]
Figure 5. The topographical features of the Met ATP binding site. A: Tyrosine in the activation loop , B: Hydrophobic sub-pocket C: Central hydrophobic region, D: Hinge region, E: Hydrophobic sub-pocket. [ 16 ]
Figure 6. SAR of class I Met inhibitors with various substitution groups. Ar symbolizes an aromatic group (in this figure, from left to right: quinoline, azaindole, benzothiazide, benzyl groups (with various R groups, such as -OH) and methoxyphenyl)). X symbolizes the linker between the core and the aryl group (from left to right: Methyl, difluoro methyl, methoxy, amino and sulfur groups). R1 symbolizes the various groups which were added onto C-7 (from top to bottom: N-linked chlorophenol, N-hydroxyethyl pyrazole and pyrazole). Atoms in positions 1, 5, 8 and 9 in many of the tested analogs were either C or N atoms. [ 12 ]
Figure 7. MK2461, a unique c-Met inhibitor
Figure 8. A common scaffold for class II Met inhibitors. Atoms in positions F, E, 6 and 3 in many of the tested analogs were either C, C-F or N groups. The O atom of the amide may be substituted for an S atom. The R groups represent some of the groups that were tested against MET with various substitution groups (Left side from top to bottom: Amide, chlorine, aryl oxy qinoline groups, methoxy phenyl and pyrrolotriazines with a terminal amine group. Right side from top to bottom: Fluorophenyl malonamide with a cyclopropyl group, hydroxy methyl phenyl pyrazolone, ethoxy fluorophenyl pyridone and fluorophenyl oxalamide).A: The R3 group lodges into the hydrophobic pocket of c-MET, B: The pyridine group binds to the hinge region and C: The R2 group usually binds to the ribose pocket where the ribose of ATP normally binds. [ 12 ]
Tivantinib (ARQ197), a c-Met inhibitor