WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 202221
CAS#: 956905-27-4 (free base)
Description: PF-04217903 is a MET tyrosine kinase inhibitor, is also a n orally bioavailabe, small-molecule tyrosine kinase inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. c-Met 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.
MedKoo Cat#: 202221
Name: PF-04217903
CAS#: 956905-27-4 (free base)
Chemical Formula: C19H16N8O
Exact Mass: 372.14471
Molecular Weight: 372.38
Elemental Analysis: C, 61.28; H, 4.33; N, 30.09; O, 4.30
Related CAS #: 956905-27-4 (free base) 956906-93-7 (mesylate)
Synonym: PF04217903; PF 04217903; PF-04217903; PF4217903; PF-4217903; PF 4217903.
IUPAC/Chemical Name: 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol
InChi Key: PDMUGYOXRHVNMO-UHFFFAOYSA-N
InChi Code: 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
SMILES Code: OCCN1N=CC(C2=CN=C3C(N(CC4=CC=C5N=CC=CC5=C4)N=N3)=N2)=C1
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | PF-04217903 is a c-Met kinase inhibitor with a Ki of 4.8 nM for human c-Met. |
| In vitro activity: | The antiangiogenic activity of PF-04217903 was evaluated in vitro. PF-04217903 inhibited HGF-stimulated c-Met phosphorylation in HUVECs with an IC50 value of 4.6 nmol/L (Supplementary Table S1). In endothelial cell functional assays, PF-04217903 inhibited HGF-mediated HUVEC survival (IC50 = 12 nmol/L), Matrigel invasion (IC50 = 27 nmol/L), and induced HUVEC apoptosis (IC50 = 7 nmol/L; Table 1). Reference: Mol Cancer Ther. 2012 Apr;11(4):1036-47. https://mct.aacrjournals.org/content/11/4/1036.long |
| In vivo activity: | PF-04217903 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. 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. Reference: Mol Cancer Ther. 2012 Apr;11(4):1036-47. https://mct.aacrjournals.org/content/11/4/1036.long |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 5.0 | 13.4 |
The following data is based on the product molecular weight 372.38 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Zou HY, 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. 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. doi: 10.1158/1535-7163.MCT-11-0839. Epub 2012 Mar 2. PMID: 22389468. |
| In vitro protocol: | 1. Zou HY, 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. 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. doi: 10.1158/1535-7163.MCT-11-0839. Epub 2012 Mar 2. PMID: 22389468. |
| In vivo protocol: | 1. Zou HY, 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. 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. doi: 10.1158/1535-7163.MCT-11-0839. Epub 2012 Mar 2. PMID: 22389468. |
1: Yan L, Zhang L, Zhang Y, Qiao X, Pan J, Liu H, Lu S, Xiang B, Lu T, Yuan H. Insight into the key features for ligand binding in Y1230 mutated c-Met kinase domain by molecular dynamics simulations. J Biomol Struct Dyn. 2017 Jun 20:1-17. doi: 10.1080/07391102.2017.1340852. [Epub ahead of print] PubMed PMID: 28599617.
2: Yu LL, Liu YJ, Wang ZH, Shi L, Liu LX. The study of endogenous hepatocyte growth factor in the pathogenesis of intracranial aneurysms. Eur Rev Med Pharmacol Sci. 2017 Feb;21(4):795-803. Retraction in: Eur Rev Med Pharmacol Sci. 2017 Mar;21(6):1176. PubMed PMID: 28272703.
3: Yeh I, Botton T, Talevich E, Shain AH, Sparatta AJ, de la Fouchardiere A, Mully TW, North JP, Garrido MC, Gagnon A, Vemula SS, McCalmont TH, LeBoit PE, Bastian BC. Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun. 2015 May 27;6:7174. doi: 10.1038/ncomms8174. PubMed PMID: 26013381; PubMed Central PMCID: PMC4446791.
4: Peña-Silva RA, Chalouhi N, Wegman-Points L, Ali M, Mitchell I, Pierce GL, Chu Y, Ballas ZK, Heistad D, Hasan D. Novel role for endogenous hepatocyte growth factor in the pathogenesis of intracranial aneurysms. Hypertension. 2015 Mar;65(3):587-93. doi: 10.1161/HYPERTENSIONAHA.114.04681. Epub 2014 Dec 15. PubMed PMID: 25510828; PubMed Central PMCID: PMC4326566.
5: Matte I, Lane D, Laplante C, Garde-Granger P, Rancourt C, Piché A. Ovarian cancer ascites enhance the migration of patient-derived peritoneal mesothelial cells via cMet pathway through HGF-dependent and -independent mechanisms. Int J Cancer. 2015 Jul 15;137(2):289-98. doi: 10.1002/ijc.29385. Epub 2014 Dec 18. PubMed PMID: 25482018.
6: Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X. Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep. 2014 Jan;9(1):83-90. doi: 10.3892/mmr.2013.1781. Epub 2013 Nov 7. PubMed PMID: 24213221.
7: Diamond JR, Salgia R, Varella-Garcia M, Kanteti R, LoRusso PM, Clark JW, Xu LG, Wilner K, Eckhardt SG, Ching KA, Lira ME, Schoenmakers EF, Christensen JG, Camidge DR. Initial clinical sensitivity and acquired resistance to MET inhibition in MET-mutated papillary renal cell carcinoma. J Clin Oncol. 2013 Jun 1;31(16):e254-8. doi: 10.1200/JCO.2012.46.4289. Epub 2013 Apr 22. PubMed PMID: 23610116; PubMed Central PMCID: PMC3661938.
8: Sennino B, Ishiguro-Oonuma T, Schriver BJ, Christensen JG, McDonald DM. Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice. Cancer Res. 2013 Jun 15;73(12):3692-703. doi: 10.1158/0008-5472.CAN-12-2160. Epub 2013 Apr 10. PubMed PMID: 23576559; PubMed Central PMCID: PMC3686901.
9: Cui JJ, 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. 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. J Med Chem. 2012 Sep 27;55(18):8091-109. Epub 2012 Sep 10. Erratum in: J Med Chem. 2012 Nov 26;55(22):10314. PubMed PMID: 22924734.
10: Lee NV, Lira ME, Pavlicek A, Ye J, Buckman D, Bagrodia S, Srinivasa SP, Zhao Y, Aparicio S, Rejto PA, Christensen JG, Ching KA. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation. PLoS One. 2012;7(6):e39653. doi: 10.1371/journal.pone.0039653. Epub 2012 Jun 22. Erratum in: PLoS One. 2012;7(8). doi: 10.1371/annotation/d988dd75-bcd2-4859-b20b-487e1bf2513b. PubMed PMID: 22745804; PubMed Central PMCID: PMC3382171.
11: Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012 Mar;2(3):270-87. doi: 10.1158/2159-8290.CD-11-0240. Epub 2012 Feb 24. PubMed PMID: 22585997; PubMed Central PMCID: PMC3354652.
12: Zou HY, 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. 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. doi: 10.1158/1535-7163.MCT-11-0839. Epub 2012 Mar 2. PubMed PMID: 22389468.
13: Dillon R, Nilsson CL, Shi SD, Lee NV, Krastins B, Greig MJ. Discovery of a novel B-Raf fusion protein related to c-Met drug resistance. J Proteome Res. 2011 Nov 4;10(11):5084-94. doi: 10.1021/pr200498v. Epub 2011 Oct 12. PubMed PMID: 21936566.
14: Yamazaki S, Skaptason J, Romero D, Vekich S, Jones HM, Tan W, Wilner KD, Koudriakova T. Prediction of oral pharmacokinetics of cMet kinase inhibitors in humans: physiologically based pharmacokinetic model versus traditional one-compartment model. Drug Metab Dispos. 2011 Mar;39(3):383-93. doi: 10.1124/dmd.110.035857. Epub 2010 Nov 23. PubMed PMID: 21098644.
15: Timofeevski SL, McTigue MA, Ryan K, Cui J, Zou HY, Zhu JX, Chau F, Alton G, Karlicek S, Christensen JG, Murray BW. Enzymatic characterization of c-Met receptor tyrosine kinase oncogenic mutants and kinetic studies with aminopyridine and triazolopyrazine inhibitors. Biochemistry. 2009 Jun 16;48(23):5339-49. doi: 10.1021/bi900438w. PubMed PMID: 19459657.
