3U6I

Crystal structure of c-Met in complex with pyrazolone inhibitor 58a

Summary for 3U6I

• Entry DOI: 10.2210/pdb3u6i/pdb
• Related: 3U6H 3U6J
• Descriptor: Hepatocyte growth factor receptor, N-{3-fluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl}-1-[(2R)-2-hydroxypropyl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (3 entities in total)
• Functional Keywords: kinase domain, phosphotransferase, cancer, hepatocyte growth factor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 1
• Total formula weight: 35758.27

Authors

Bellon, S.F.,Whittington, D.A.,Long, A.L. (deposition date: 2011-10-12, release date: 2012-02-22, Last modification date: 2023-09-13)

Primary citation

Norman, M.H.,Liu, L.,Lee, M.,Xi, N.,Fellows, I.,D'Angelo, N.D.,Dominguez, C.,Rex, K.,Bellon, S.F.,Kim, T.S.,Dussault, I.
Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.
J.Med.Chem., 55:1858-1867, 2012

PubMed Abstract: Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.

PubMed: 22320343
DOI: 10.1021/jm201330u

Experimental method

X-RAY DIFFRACTION (2.1 Å)