Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening.
Hepatocyte growth factor (HGF) is an important regulator of normal development and homeostasis, and dysregulated signaling through the HGF receptor, Met, contributes to tumorigenesis, tumor progression, and metastasis in numerous human malignancies. The development of selective small-molecule inhibitors of oncogenic tyrosine kinases (TK) has led to well-tolerated, targeted therapies for a growing number of cancer types. To identify selective Met TK inhibitors, we used a high-throughput virtual screen of the 13.5 million compound ChemNavigator database to find compounds most likely to bind to the Met ATP binding site and to form several critical interactions with binding site residues predicted to stabilize the kinase domain in its inactive conformation. Subsequent biological screening of 70 in silico hit structures using cell-free and intact cell assays identified three active compounds with micromolar IC(50) values. The predicted binding modes and target selectivity of these compounds are discussed and compared to other known Met TK inhibitors.
Peach
Megan L
ML
Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
Tan
Nelly
N
Choyke
Sarah J
SJ
Giubellino
Alessio
A
Athauda
Gagani
G
Burke
Terrence R
TR
Nicklaus
Marc C
MC
Bottaro
Donald P
DP
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met