Drugs in Clinical Pipeline: Foretinib | EXEL-2880 | HGF, VEGF Inhibitor | Multi-Kinase Inhibitor | Angiogenesis Inhibitor

Foretinib [N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide] is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor β, and Tie-2. Binding of Foretinib to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft [1].

Foretinib: 2D and 3D Structure

Foretinib inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and inhibits growth of tumor cells under both normoxic and hypoxic conditions with increased potency against Met-amplified gastric cancer cell lines. In vitro, Foretinib inhibits HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells that are thought to contribute to invasion, metastasis, and angiogenesis in vivo. Consistent with this profile, Foretinib inhibits tumor formation in an in vivo murine model of lung metastasis. Foretinib therefore has the potential to prevent tumor growth through a direct effect on tumor cell proliferation and indirectly through inhibition of the host angiogenic response.

Using high-throughput unbiased screening approach to identify small-molecule kinase inhibitors with potent activity against orphan RTK c-ros oncogene 1 (ROS1), researchers found that Foretinib is a highly effective inhibitor of ROS1 in human and murine model systems, demonstrating greater potency compared with Crizotinib both in vitro and in vivo. Despite the reported binding affinity (K_d) of Crizotinib for ROS1 being lower than that of Foretinib (4.4 nM and 14 nM, respectively), researchers found Foretinib to be a significantly more potent ROS1 inhibitor in cell-based assays, accentuating that the in vitro binding affinity does not directly translate to inhibitory efficacy in the cellular context.

Exelixis is credited with discovering Foretinib. It was called EXEL-2880 at Exelixis. Subsequently, the compound was licensed to GlaxoSmithKline in December 2007 where it was called GSK1363089. It is in Phase II trials for various cancers.

The activity of Foretinib is as follows:

IC₅₀ (Met enzyme assay) = 0.4 ± 0.04 nM

IC₅₀ (Ron enzyme assay) = 3 ± 0.2 nM

IC₅₀ (KDR enzyme assay) = 0.86 ± 0.04 nM

IC₅₀ (Flt-1 enzyme assay) = 6.8 ± 0.7 nM

IC₅₀ (Flt-4 enzyme assay) = 2.8 ± 0.4 nM

IC₅₀ (KIT enzyme assay) = 6.7 ± 0.6 nM

IC₅₀ (Flt-3 enzyme assay) = 3.6 ± 0.4 nM

IC₅₀ (PDGFR-α enzyme assay) = 3.6 ± 0.4 nM

IC₅₀ (PDGFR-β enzyme assay) = 9.6 ± 1.1 nM

IC₅₀ (Tie-2 enzyme assay) = 1.1 ± 0.1 nM

IC₅₀ (FGFR1 enzyme assay) = 660 ± 50 nM

IC₅₀ (EGFR enzyme assay) = 2990 ± 38 nM


Common Name: Foretinib

Synonyms: XL880; XL 880; XL-880; EXEL-2880; GSK1363089; GSK 1363089; GSK-1363089; SK1363089; GSK089

IUPAC Name: N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

CAS Number: 849217-64-7

SMILES: 

Mechanism of Action: Kinase Inhibitor; Multi-Kinase Inhibitor; MET Kinase Inhibitor; KDR Inhibitor

Indication: Various Cancers; Anti-tumor Agents; Angiogenesis Inhibitor

Development Stage: Phase II

Company: Exelixis Inc/GlaxoSmithKline

1H NMR (Estimated) for Foretinib

References:
1. Qian, F.; et. al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009, 69(20), 8009-8016.

Drugs in Clinical Pipeline: BMS-794833

BMS-794833 [N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide] is a potent ATP competitive inhibitor of Met/VEGFR2 kinases with IC₅₀ of 1.7 nM/15 nM, respectively [1]. 

BMS-794833 also inhibits Ron (Met family), Axl (phylogenetically related Axl/Tyro3/Mer subfamily) and Flt-3 with IC₅₀ values less than 3 nM. The compound was selective versus a panel of greater than 200 additional receptor tyrosine kinase (RTKs), non-RTKs and serine/threonine kinases based on biochemical or Ambit binding assays. Moreover, it inhibited the cell growth in GTL-16 gastric carcinomas with an IC₅₀ of 39 nM [1, 2].

In vivo, BMS-794833 exhibited dose-dependent anti-tumor activity against multiple tumor types without overt toxicities at efficacious dose levels. The dual kinase inhibition capability coupled with these findings support the utility of BMS-794833 as an anti-cancer therapeutic agent which has been nominated for clinical development [3].

In Nov 2010, BMS-817378 (CAS # 1025720-94-8) which is a prodrug of BMS-794833 was licensed to Simcere Pharmaceutical Group in China. Simcere obtained the rights for development and commercialization of this product in China. Simcere is presently pursuing Phase I trial for the same.

The activity of BMS-794833 is as follows:

IC₅₀ (MET enzyme assay) = 1.7 nM

IC₅₀ (VEGFR2 enzyme assay) = 15 nM

                                                                                                                      

Common Name: BMS-794833

Synonyms: BMS-794833; BMS794833; BMS 794833

IUPAC Name: N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide

CAS Number: 1174046-72-0

SMILES: 

Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor; KDR Inhibitor; VEGFR2 Inhibitor; Angiogenesis Inhibitor

Indication: Various Cancers

Development Stage: Phase I (Study was withdrawn)

Company: Bristol Myers Squibb/Simcere Pharmaceuticals

Met receptor tyrosine kinase (RTK) is expressed predominantly on epithelial and endothelial cells, and serves as the only known high-affinity receptor for the mesenchyme-derived ligand, hepatocyte growth factor (HGF). Met activation can occur via ligand binding, receptor overexpression, and/or activating mutations. Subsequent signal transduction leads to complex biological responses, such as cellular proliferation, motility, migration, invasion, survival, morphogenesis and angiogenesis. Dysregulated Met/HGF signaling promotes tumor formation, growth, proliferation and metastasis, and thus, has been implicated in a wide array of human malignancies. Clinically, Met expression has been shown to be an independent prognostic factor in breast cancer, and increased levels of circulating HGF and/or Met expression have been detected in patients with tumors of diverse histological origins. Furthermore, elevated levels of Met and/or HGF strongly correlate with poor patient prognosis. These findings suggest that Met and HGF are viable candidates for targeted cancer therapies.

Tumor cell lines whose growth is stimulated by HGF (U87 glioblastoma) were also effectively inhibited by BMS-794833. In vivo, BMS-794833 demonstrated dose-dependent tumor growth inhibition following oral administration in the GTL-16 and L2987 lung carcinoma (Met-insensitive) xenograft models. Despite the impressive antitumor activity, BMS-794833 showed dissolution rate-limited absorption from solid dosage forms. The phosphooxymethyl prodrug, BMS-817378 was found to effectively liberate BMS-794833 in various in vitro and in vivo systems. On the basis of its desirable pharmacological profile, acceptable in vitro ADME and safety characteristics, and favorable pharmacokinetic properties in multiple species, BMS-817378 was selected for clinical development [2].

References:

1. Borzilleri, R. M.; et. al. 4-pyridinone compounds and their use for cancer. WO2009094417A1.
2. Borzilleri; R.; et. al. Discovery of BMS-817378- a novel prodrug of the dual Met/VEGFR-2. Eur J Can Supp 2010, 8(7), 38.
3. Fargnoli, J.; et. al. Preclinical studies and characterization of BMS-794833, a small molecule inhibitor of Met and VEGFR-2 kinases. Eur J Can Supp 2010, 8(7), 41.

4. Tiedt, R.; et. al. Tyrosine kinase inhibitor combinations and their use. WO2013151913A1 (for structure of BMS-817378)

5. ClinicalTrials.gov Ascending Multiple-Dose Study of BMS-817378 in Subjects With Advanced Cancers. NCT00792558 (retrieved on 17-09-2015)

Drugs in Clinical Pipeline: SGX523

SGX523 [6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo-[4,3-b]pyridazin-3-ylsulfanyl] quinoline] is an orally bio-available, ATP competitive, small molecule inhibitor of MET, binding the kinase domain active site in a novel mode. 

SGX523 potently inhibited MET with an IC₅₀ of 4 nM and is greater than 1000-fold selective versus more than 200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity [1]. SGX523 is therefore ideally suited to understand the role of MET catalytic activity in tumorigenesis without the confounding effects of off-target kinase inhibition.

SGX523 showed ATP-competitive inhibition with higher apparent affinity for the less active, unphosphorylated form of MET (K_i = 2.7 nM) versus the more active phospho-enzyme (K_i = 23 nM), a phenomenon consistent with preferential binding to an inactive enzyme conformation. Enzymatic studies showed that SGX523 potently inhibits the purified MET catalytic domain but not the closely related receptor tyrosine kinase RON. The kinase selectivity profile of SGX523 was assayed against 213 protein kinases, including wild-type and mutant (Met^1268Thr) MET. In this assay, SGX523 inhibits wild-type MET with an IC₅₀ of 4 nM. At a screening concentration of 1 uM, no protein kinase from the panel, other than MET or MET^Met1268Thr, was inhibited by greater than 36%. Formal IC₅₀ determinations were conducted for the five most sensitive kinases (BRAF, ABL, RAF1, MAPK14, ABL1^Y253F). No significant enzyme inhibition was observed, even at compound concentrations from 7 uM and more [1].

The activity of SGX523 is as follows:

IC₅₀ (MET enzyme assay) = 4 nM

Common Name: SGX523

Synonyms: SGX-523; SGX523; SGX523

IUPAC Name: 6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)thio) quinoline

CAS Number: 1022150-57-7

Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor

Indication: Various Cancers; Solid Tumors

Development Stage: Phase I. Drug development has been stopped.

Company: SGX Pharmaceuticals

Hepatocyte growth factor (HGF) receptor, c-Met, or MET, is the prototypic member of a family of receptor tyrosine kinases unique to deuterostomes. MET orchestrates the complex program of branching morphogenesis, which is critical during embryonic development and tissue repair and for invasive growth in cancer. Activating point mutations in the MET gene are found in hereditary and sporadic forms of papillary renal carcinoma and gene amplification leads to upregulated MET signaling in other tumors, notably in the context of acquired resistance to epidermal growth factor receptor inhibitors in lung cancer. In other malignancies, such as glioblastoma, autocrine activation of MET by HGF has been shown, and MET inhibition is effective in mouse models of glioblastoma.

Phase I Study [3]

Methodology

Two phase 1, open-label, dose-escalation studies of SGX523 were conducted to evaluate both interrupted and continuous dosing schedules. Thirty-six patients per study were planned to be enrolled. The first study explored a 21-day cycle with SGX523 administered on an intermittent schedule at a starting dose of 60 mg PO BID for 14 days followed by 7 days of rest. The second protocol explored a continuous 28-day dosing schedule with SGX523 administered at a starting dose of 20 mg PO BID for 28 days without rest.

Results

A total of 10 patients were enrolled, 2 on the intermittent dosing protocol and 8 on the continuous dosing protocol. All 6 patients that received daily doses of = 80 mg developed unexpected renal failure manifested by an early rise of serum blood urea nitrogen and creatinine. Human PK analysis revealed the formation of two insoluble metabolites at levels not seen in the rat or dog preclinical toxicology studies. Subsequent primate toxicology and toxicokinetic evaluation replicated human findings, and histological examination of the monkey kidneys revealed the formation of crystals both within the renal tubules and within giant cell macrophages.

Conclusion

Primate toxicology studies suggest the cause of the renal failure seen in humans was a crystal nephropathy secondary to insoluble metabolites. SGX523 is no longer in clinical development.

References:
1. Buchanan, S. G.; et. al. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther 2009, 8(12), 3181-3190.
2. ClinicalTrials.gov Safety Study of SGX523, a Small Molecule Met Inhibitor, to Treat Solid Tumors. NCT00607399 (retrieved 01-08-2015)
3. Infante, J. R.; et. al. Unexpected renal toxicity associated with SGX523, a small molecule inhibitor of MET. Invest New Drugs 2013, 31(2), 363-369.

Drugs in Clinical Pipeline: Savolitinib

Savolitinib [(S)-1-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine] is an orally available, small-molecule, highly selective c-Met inhibitor (IC₅₀ = 0.005 uM). The structure-activity relationship in a series of novel triazolopyrazine c-Met inhibitors was investigated, leading to the identification of Savolitinib, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice. Savolitinib is a potent ATP-competitive c-Met inhibitor with high selectivity over a 274-kinase panel. It is being developed as an oral tablet for the treatment of solid tumors [1].

In December 2011, AstraZeneca and Hutchison Medi Pharma have signed a global licensing, co-development, and commercialization agreement for Savolitinib.

The activity of Savolitinib is as follows:

IC₅₀ (c-Met enzyme assay) = 0.005 uM

IC₅₀ (p-Met Cell Based assay) = 0.003 uM

Common Name: Savolitinib

Synonyms: HMPL-504; HMPL 504; HMPL504; AZD6094; AZD-6094; AZD 6094; Volitinib

IUPAC Name: (S)-1-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine

CAS Number: 1313725-88-0

Mechanism of Action: Kinase Inhibitor; c-Met Inhibitor

Indication: Various Cancers; Solid Tumors

Development Stage: Phase II

Company: Hutchison Medi Pharma (China)/AstraZeneca

References:

1. Jia, H.; et. al. Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer. J Med Chem 2014, 57(18), 7577-7589.

Drugs in Clinical Pipeline: AMG-208

AMG 208 [4-[(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]-7-methoxy quinoline] is a potent and highly selective small molecule ATP-competitive MET kinase inhibitor that demonstrates good cellular activity. 

AMG 208 was born using an imaginative skill by the researchers at Amgen. Starting with a binding model of in-house an efficient c-Met inhibitor with a pyrimidinone moiety (1, IC₅₀ = 10 nM) and overlapping with that of triazolopyridazine (2, IC₅₀ = 120 ± 18 nM), researchers at Amgen designed a potent triazolopyridazine quinoline c-Met inhibitor, AMG-208 (IC₅₀ = 9 ± 2 nM) [1]. Furthermore, AMG 208 inhibited HGF-mediated c-Met phosphorylation in PC3 cells with IC₅₀ value of 46 ± 11 nM.

AMG 208 inhibits both ligand-dependent and ligand-independent c-Met cellular growth regulation. Inhibition of c-Met signaling with AMG 208 provides a potential mechanism for blocking tumor growth and survival.

Common Name: AMG-208

Synonyms:  AMG-208; AMG 208;AMG208

IUPAC Name: 4-[(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]-7-methoxyquinoline

CAS Number: 1002304-34-8

SMILES: COC1=CC2=NC=CC(=C2C=C1)OCC3=NN=C4N3N=C(C=C4)C5=CC=CC=C5

Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor

Indication: Various Cancers; Anti-Tumor Therapy

Development Stage: Phase II

Company: Amgen Inc

The receptor tyrosine kinase c-Met and its natural ligand, hepatocyte growth factor (HGF), are involved in cell proliferation, migration, and invasion and are essential for normal embryonic development. Deregulation of c-Met/HGF signaling can lead to tumorigenesis and metastasis and has been implicated in a variety of cancers. Several mechanisms lead to deregulation, including overexpression of c-Met and/or HGF, amplification of the MET gene, or activating mutations of c-Met, all of which have been found in human cancers.

Phase I Study

A phase 1, first-in-human study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of AMG 208 in adult subjects with advanced solid tumors it was observed that AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer [2,3].

Methodology

Using a modified Fibonacci design, 3-9 patients (18 yr and above, advanced solid tumors, ECOG = 2, and evaluable/measurable disease) were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Patients received AMG 208 orally on days 1 and 4-28 once daily. If no dose limiting toxicity (DLT) was seen on days 1-28, patients received AMG 208 once daily starting at day 36 provided patients showed no evident disease progression. In cohorts 1-3, a standard 3+3 design was followed. In cohorts 4-7, a modified 3+3+3 design was followed.

Results

Fifty four patients (67% were men; 19% had prostate cancer (PC) received dose of AMG 208. Median (range) age was 61 (39-80) year with ECOG 0/1 as 52%/48%. Six DLTs were seen: a grade (G) 3 increased AST (200 mg), a G3 thrombocytopenia (200 mg), a G4 acute myocardial infarction (300 mg), a G3 prolonged QT (300 mg), and two G3 hypertensions (400 mg). The maximum tolerated dose was not reached. 83% of patients had tx-related adverse events (AE). Tx-related AE occurring in greater than 10 patients: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of patients had grade = 3 tx-related AE.

AMG 208 was orally bioavailable with a 30-35 hr mean half-life in plasma. Exposure increased linearly with dose; accumulation at day 28 was 2.7-fold across cohorts. Of the 42 patients with available tumor response data for site reads, 1 had complete response on bone scan (PC 300 mg) while 2 had partial responses (PR; PC 400 mg and kidney cancer 200 mg; both had -33% tumor shrinkage), and 29 had stable disease (SD); 1 other PC patient had PR after data cutoff. Of the 35 patients with available tumor response data for central reads, 26 had SD.

References:

1. Albrecht, B. K.; et. al. Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase. J Med Chem 2008, 51(10), 2879-2882.
2. Hong, D. S.; et. al. First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors. J Clin Oncol 2013, 31(suppl 6; abstr 41).
3. ClinicalTrials.gov A Phase 1 Study of AMG 208 in Subjects With Advanced Solid Tumors. NCT00813384 (retrieved 10-06-2015)

Drugs in Clinical Pipeline: AMG-337

AMG 337 is a potent and highly selective small molecule ATP-competitive MET kinase inhibitor that demonstrates robust activity in MET-dependent cancer models. In enzymatic assays, AMG 337 inhibited MET kinase activity with an IC₅₀ less than 5 nM. AMG 337 demonstrated exquisite selectivity for MET when profiled against a diverse panel of over 400 protein and lipid kinases in a competitive binding assay. In cellular assays, AMG 337 inhibited HGF-dependent MET phosphorylation with an IC₅₀ of less than 10 nM [1].

AMG 337 was profiled in cell viability assays using a diverse panel of over 200 cancer cell lines where on treatment with AMG 337 affected the viability of only two gastric cancer cell lines (SNU-5 and Hs746T), both of which harbor amplification of the MET gene. The AMG 337 IC₅₀ in the two sensitive cell lines was less than 50 nM, and greater than 10 µM in all other tested cell lines.

Common Name: AMG-337

Synonyms:  AMG337; AMG 337; AMG-337

IUPAC Name: -

CAS Number: -

SMILES: -

Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor

Indication: Various Cancers; Anti-Tumor Therapy

Development Stage: Phase II

Company: Amgen Inc

The receptor tyrosine kinase c-Met and its natural ligand, hepatocyte growth factor (HGF), are involved in cell proliferation, migration, and invasion and are essential for normal embryonic development. Deregulation of c-Met/HGF signaling can lead to tumorigenesis and metastasis and has been implicated in a variety of cancers. Several mechanisms lead to deregulation, including overexpression of c-Met and/or HGF, amplification of the MET gene, or activating mutations of c-Met, all of which have been found in human cancers.

AMG 337 is a potent and highly selective inhibitor of wild-type and some mutant forms of MET. In a competitive binding assay conducted on 402 human kinases, AMG 337 bound only to MET. In a cell viability study, the only cell lines that responded to an AMG 337 analog were gastric cancer cells harboring MET gene amplification. None of the other cell lines were sensitive to the AMG 337 analog and none harbored MET gene amplification. In secondary pharmacology assays with transporters, enzymes, ion channels, and receptors, binding to the adenosine transporter was the only activity inhibited.

In vivo, oral administration of AMG 337 resulted in robust dose-dependent anti-tumor efficacy in MET amplified gastric cancer xenograft models, with inhibition of tumor growth consistent with the pharmacodynamic modulation of MET signaling. Further studies in an expanded panel of additional cancer cell lines derived from gastric, NSCLC, and esophageal cancer confirmed that the in-vitro anti-proliferative activity of AMG 337 correlated with amplification of MET. In those cell lines, treatment with AMG 337 inhibited downstream PI3K and MAPK signaling pathways, which translated into growth arrest as evidenced by an accumulation of cells in the G1 phase of the cell cycle, a concomitant reduction in DNA synthesis, and the induction of apoptosis [1].

In a small subset of patients with MET-amplified gastrointestinal (GI) tumors, monotherapy with the investigational agent AMG 337 produced a "dramatic" response. Of the 13 patients with MET-amplified gastric and esophageal cancers, eight experienced a response. The overall response rate in this group of patients was 62%. Response was rapid, with time to response being 4 weeks in most cases. Patients achieved tumor shrinkage and symptomatic improvement. One patient achieved a complete response and is still on treatment at 155 weeks; the others achieved partial responses or stable disease. This has led to further trials, including Phase II trials MET amplified gastric/esophageal adenocarcinoma or other solid tumors.

Structure of AMG 337

Till date Amgen has not disclosed the structure for AMG 337. Taking clue for AMG 208, and publications in various articles, one of the possible candidates for AMG 337 can be:

The profile of the molecule matches to those of the Amgen has released for AMG 337. The inhibition of kinase activity (IC₅₀ = 5 nM) and inhibition of HGF-mediated c-Met phosphorylation in PC3 cells (IC₅₀ = 3 nM) are reported [2]. It appears to be an excellent strategy on part of Amgen, where AMG 208 uses O-linked triazolopyridazines, AMG 337 uses N-linked triazolopyridazines, thereby covering a good patent space.

One another possible structure for AMG-337 as suggested by few others is:

It is claimed to be released by Amgen but it is not confirmed. Moreover, no citation is provided. Need to look into it as well.

References:
1. Hughes, P. E.; et. al. Abstract 728: AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models. Cancer Res 2014, 74, 728.
2. Boezio, A. A.; et. al. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. Bioorg Med Chem Lett 2009, 19(22), 6307-6312.
3. ClinicalTrials.gov Phase 2 Study of AMG 337 in MET Amplified Gastric/Esophageal Adenocarcinoma or Other Solid Tumors. NCT02016534 (retrieved 10-06-2015)
4. ClinicalTrials.gov A Study of AMG 337 in Subjects With Advanced Solid Tumors. NCT01253707 (retrieved 10-06-2015)

Drugs in Clinical Pipeline: SAR125844

SAR125844 [1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea] is a potent and selective small molecule inhibitor of MET receptor tyrosine kinase with potential therapeutic application in cancer patients having deregulated MET-dependent malignancies. SAR125844 displayed nanomolar activity against the wild-type MET kinase (IC₅₀ = 4.2 nM) and the M1250T and Y1235D mutants [1,4]. 

Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase in a panel of 275 kinases tested, with only 5 other protein kinases inhibited at IC₅₀ values below 300 nM (CDK9 greater than 10 uM). SAR125844 exhibits also satisfactory eADMET in vitro properties and has shown moderate total plasma clearance, large volume of distribution and moderate to long terminal elimination half-life in rats.

SAR125844 is a Biopharmaceutics Classification System (BCS) class IV due to its very poor solubility in water (less than 0.1 µg mL) and poor permeability characteristics, thus developed for intravenous administration to overcome the permeability issue. In vitro it has highly potent nanomolar anti-proliferative activity on human Met- driven tumor cell lines exclusively. The cellular anti-tumor activity as a single agent in human Met-amplified models is also highly potent [2].

Common Name: SAR125844

Synonyms: SAR125844; SAR 125844; SAR-125844

IUPAC Name: 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea

CAS Number: 1116743-46-4

SMILES: -

Mechanism of Action: MET Kinase Inhibitor

Indication: Various Cancers; Anti-Tumor Therapy

Development Stage: Phase I

Company: Sanofi

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

In cellular assays, SAR125844 inhibits MET autophosphorylation at the nanomolar range (IC₅₀ from 1.4 to 5.1 nM), translating into antiproliferative activity selectively in MET-driven cell lines such as MET-amplified cell lines, with IC₅₀ values in the low nanomolar range and induction of apoptosis. SAR125844 induces a G1 block in the two MET-amplified tumor cell lines tested. Moreover, the compound is also able to inhibit HGF-induced cell migration in PC-3 prostate tumor cell line. In two MET-amplified human gastric tumor xenograft models tested, SNU-5 and Hs 746T, SAR125844 intravenous treatment leads to potent impact on the MET signaling pathway in a dose and time dependent manner, with potent inhibition of MET autophosphorylation, as well as a significant effect on downstream PI3K/AKT and RAS/MAPK pathways. As a single agent, this translates into a dose-dependent antitumor activity in these two xenograft models, with tumor stasis at the lowest active dose and tumor regression at the highly active doses. High loading single dose administration of SAR125844 using a nanosuspension formulation allowed a sustained P-MET inhibition in tumors up to 7 days. In all models, antitumor activity was achieved at well tolerated doses without significant effect on body weight [3,4].

References:
1. Schio, J.; et. al. Abstract 2911: SAR125844: a potent and selective ATP-competitive inhibitor of MET kinase. Cancer Res 2012, 72, 2911.
2. Authelin, J.-R.; et. al. Anti-tumoral composition comprising the compound 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea. WO2014009500A1.
3. Goulaouic, H.; et. al. Abstract 845: In vitro and in vivo pharmacology of SAR125844, a potent and selective intravenous MET kinase inhibitor undergoing Phase I clinical trial. Cancer Res 2012, 72, 845.
4. Goulaouic, H.; et. al. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. Mol Cancer Ther 2015, 14(2), 384-394.