Thursday, June 11, 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 ┬ÁM 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)