3ZXZ

X-ray Structure of PF-04217903 bound to the kinase domain of c-Met

Summary for 3ZXZ

• Entry DOI: 10.2210/pdb3zxz/pdb
• Related: 1FYR 1R0P 1R1W 1SHY 1SSL 1UX3 2CEW 2G15 2UZX 2UZY 2WD1 2WGJ 2WKM 3ZZE 4AOI 4AP7
• Descriptor: HEPATOCYTE GROWTH FACTOR RECEPTOR, 2-{4-[1-(QUINOLIN-6-YLMETHYL)-1H-[1,2,3]TRIAZOLO[4,5-B]PYRAZIN-6-YL]-1H-PYRAZOL-1-YL}ETHANOL (3 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 35251.80

Authors

McTigue, M.,Grodsky, N.,Ryan, K.,Cui, J.J. (deposition date: 2011-08-16, release date: 2011-08-31, Last modification date: 2023-12-20)

Primary citation

Cui, J.J.,Mctigue, M.,Nambu, M.,Tran-Dube, M.,Pairish, M.,Shen, H.,Jia, L.,Cheng, H.,Hoffman, J.,Le, P.,Jalaie, M.,Goetz, G.H.,Ryan, K.,Grodsky, N.,Deng, Y.,Parker, M.,Timofeevski, S.,Murray, B.W.,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., 55:8091-, 2012

PubMed Abstract: 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.

PubMed: 22924734
DOI: 10.1021/JM300967G

Experimental method

X-RAY DIFFRACTION (1.8 Å)