PF-04217903

• CAT Number: I008498
• CAS Number: 956905-27-4
• Molecular Formula: C19H16N8O
• Molecular Weight: 372.38
• Purity: ≥95%
• Synonyms: 2-[4-[3-(quinolin-6-ylmethyl)triazolo[4,5-b]pyrazin-5-yl]pyrazol-1-yl]ethanol
• InChI: InChI=1S/C19H16N8O/c28-7-6-26-12-15(9-22-26)17-10-21-18-19(23-17)27(25-24-18)11-13-3-4-16-14(8-13)2-1-5-20-16/h1-5,8-10,12,28H,6-7,11H2
• InChIKey: PDMUGYOXRHVNMO-UHFFFAOYSA-N
• SMILES: C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1

PF-04217903 is a potent ATP-competitive c-Met kinase inhibitor with Ki of 4.8 nM for human c-Met. PF-04217903 shows more than 1,000-fold selectivity relative to 208 kinases. Antiangiogenic properties[1][2].
PF-04217903 (0.1-10000 nM; 48-72 hours) inhibits proliferation of c-Met–amplified human GTL-16 gastric carcinoma and H1993 NSCLC cells with IC50 values of 12 and 30 nM, respectively[1].
PF-04217903 (1.5-3333 nM; 48 hours) induces apoptosis of GTL-16 cells (IC50=31 nM)[1].
PF-04217903 also inhibits HGF-mediated cell migration and Matrigel invasion in several c-Met–overexpressing tumor cell lines such as human NCI-H441 lung carcinoma and HT29 colon carcinoma with IC50 values comparable with those for inhibition of c-Met phosphorylation in these cell lines (IC50=7-12.5 nM)[1].
PF-04217903 displays similar potency to inhibit the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I with IC50 of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, but has no inhibitory activity against c-Met-Y1230C with IC50 of >10 μM[3].
PF-04217903 (1-30 mg/kg; p.o.; daily for 16 days) shows dose-dependent tumor growth inhibition, which correlated with the inhibition in c-Met phosphorylation in these tumors[1].
PF-04217903 (5-50 mg/kg, p.o.; once daily for 3 days) dose dependently inhibits c-Met, Gab-1, Erk1/2, and AKT phosphorylation and induced apoptosis (cleaved caspase-3) in U87MG xenograft tumors at all dose levels. PF-04217903 phenolsulfonate shows a significant dose-dependent reduction of human IL-8 levels in both the U87MG and GTL-16 models and decreases human VEGFA levels in the GTL-16 model. PF-04217903 strongly induces phospho-PDGFRβ levels in U87MG xenograft tumors[1].

Reference

[1]. Zou HY, et al. Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor. Mol Cancer Ther. 2012 Apr;11(4):1036-47.
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[2]. Cui JJ, et al. Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)
 [Content Brief]

[3]. Timofeevski SL, et al. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry, 2009, 48(23), 5339-5349.
 [Content Brief]