Thursday, September 17, 2015

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
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Development Stage: Phase I (Study was withdrawn)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].

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 20108(7), 41.
4. Tiedt, R.; et. al. Tyrosine kinase inhibitor combinations and their use. WO2013151913A1 (for structure of BMS-817378)
5. Ascending Multiple-Dose Study of BMS-817378 in Subjects With Advanced Cancers. NCT00792558 (retrieved on 17-09-2015)