2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol White to off white powder Others MET Tyrosine Kinase Inhibitor PF-04217903 is an orally bioavailabe, small-molecule tyrosine kinase inhibitor with potential antineoplastic activity. MET tyrosine kinase inhibitor PF-04217903 selectively binds to and inhibits c-Met, disrupting the c-Met signaling pathway, which may result in the inhibition of tumor cell growth, migration and invasion of tumor cells, and the induction of death in tumor cells expressing c-Met. The receptor tyrosine kinase c-Met, also known as hepatocyte growth factor (HGF) receptor, is overexpressed or mutated in many tumor cell types, playing an important role in tumor cell proliferation, survival, invasion, and metastasis and angiogenesis.
2-[4-[3-(6-quinolinylmethyl)-5-triazolo[4,5-b]pyrazinyl]-1-pyrazolyl]ethanol is a member of quinolines.
PF-04217903 has been used in trials studying the treatment of Neoplasms. 372.4 g/mol

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Formulation: 372.4 g/mol

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2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol

The product is for non-human research only. Not for therapeutic or veterinary use.

Catalog Number: BT-254313

CAS Number: 1159490-85-3

Molecular Formula: C19H16N8O

Molecular Weight: 372.4 g/mol

CAS Number	1159490-85-3
Product Name	2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol
Molecular Formula	C19H16N8O
Molecular Weight	372.4 g/mol
Appearance	White to off white powder
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
InChI Key	PDMUGYOXRHVNMO-UHFFFAOYSA-N
IUPAC Name	2-[4-[3-(quinolin-6-ylmethyl)triazolo[4,5-b]pyrazin-5-yl]pyrazol-1-yl]ethanol
Canonical SMILES	C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1
Description	MET Tyrosine Kinase Inhibitor PF-04217903 is an orally bioavailabe, small-molecule tyrosine kinase inhibitor with potential antineoplastic activity. MET tyrosine kinase inhibitor PF-04217903 selectively binds to and inhibits c-Met, disrupting the c-Met signaling pathway, which may result in the inhibition of tumor cell growth, migration and invasion of tumor cells, and the induction of death in tumor cells expressing c-Met. The receptor tyrosine kinase c-Met, also known as hepatocyte growth factor (HGF) receptor, is overexpressed or mutated in many tumor cell types, playing an important role in tumor cell proliferation, survival, invasion, and metastasis and angiogenesis. 2-[4-[3-(6-quinolinylmethyl)-5-triazolo[4,5-b]pyrazinyl]-1-pyrazolyl]ethanol is a member of quinolines. PF-04217903 has been used in trials studying the treatment of Neoplasms.
Other CAS Number	956905-27-4
SMILES	C1=CC2=C(C=CC(=C2)CN3C4=NC(=CN=C4N=N3)C5=CN(N=C5)CCO)N=C1
Synonyms	PF-04217903; PF 04217903; PF04217903; 2-{4-[1-(6-Quinolinylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl}ethanol
Reference	1. J Med Chem. 2012 Sep 27;55(18):8091-109. Epub 2012 Sep 10. 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)-1H-pyrazol-1 -yl)ethanol (PF-04217903) for the treatment of cancer. Cui JJ(1), McTigue M, Nambu M, Tran-Dubé M, Pairish M, Shen H, Jia L, Cheng H, Hoffman J, Le P, Jalaie M, Goetz GH, Ryan K, Grodsky N, Deng YL, Parker M, Timofeevski S, Murray BW, Yamazaki S, Aguirre S, Li Q, Zou H, Christensen J. Author information: (1)La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, USA. jean.cui@pfizer.com Erratum in J Med Chem. 2012 Nov 26;55(22):10314. The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1 -yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting. 2. Mol Cancer Ther. 2012 Apr;11(4):1036-47. doi: 10.1158/1535-7163.MCT-11-0839. Epub 2012 Mar 2. Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor. Zou HY(1), Li Q, Lee JH, Arango ME, Burgess K, Qiu M, Engstrom LD, Yamazaki S, Parker M, Timofeevski S, Cui JJ, McTigue M, Los G, Bender SL, Smeal T, Christensen JG. Author information: (1)PGRD-La Jolla, Pfizer, Inc., San Diego, California 92121, USA. helen.zou@pfizer.com The c-Met pathway has been implicated in a variety of human cancers for its critical role in tumor growth, invasion, and metastasis. PF-04217903 is a novel ATP-competitive small-molecule inhibitor of c-Met kinase. PF-04217903 showed more than 1,000-fold selectivity for c-Met compared with more than 150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 inhibited tumor cell proliferation, survival, migration/invasion in MET-amplified cell lines in vitro, and showed marked antitumor activity in tumor models harboring either MET gene amplification or a hepatocyte growth factor (HGF)/c-Met autocrine loop at well-tolerated dose levels in vivo. Antitumor efficacy of PF-04217903 was dose-dependent and showed a strong correlation with inhibition of c-Met phosphorylation, downstream signaling, and tumor cell proliferation/survival. In human xenograft models that express relatively high levels of c-Met, complete inhibition of c-Met activity by PF-04217903 only led to partial tumor growth inhibition (38%-46%) in vivo. The combination of PF-04217903 with Recepteur d/'origine nantais (RON) short hairpin RNA (shRNA) knockdown in the HT29 model that also expresses activated RON kinase-induced tumor cell apoptosis and resulted in enhanced antitumor efficacy (77%) compared with either PF-04217903 (38%) or RON shRNA alone (56%). PF-04217903 also showed potent antiangiogenic properties in vitro and in vivo. Furthermore, PF-04217903 strongly induced phospho-PDGFRβ (platelet-derived growth factor receptor) levels in U87MG xenograft tumors, indicating a possible oncogene switching mechanism in tumor cell signaling as a potential resistance mechanism that might compromise tumor responses to c-Met inhibitors. Collectively, these results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms of c-Met dysregulation. 3. PLoS One. 2012;7(6):e39653. doi: 10.1371/journal.pone.0039653. Epub 2012 Jun 22. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation. Lee NV(1), Lira ME, Pavlicek A, Ye J, Buckman D, Bagrodia S, Srinivasa SP, Zhao Y, Aparicio S, Rejto PA, Christensen JG, Ching KA. Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a MEK inhibitor, PD-0325901 (MEKi) alone effectively blocked ERK phosphorylation and inhibited cell growth. Our results suggest that combination of a c-Met tyrosine kinase inhibitor with a BRAF or a MEK inhibitor may be effective in treating resistant tumors that use activated BRAF to escape suppression of c-Met signaling.
PubChem Compound	2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol
Last Modified	May 11 2023

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