Directed discovery of agents targeting the met tyrosine kinase domain by virtual screening

Megan L. Peach, Nelly Tan, Sarah J. Choyke, Alessio Giubellino, Gagani Athauda, Terrence R. Burke, Marc C. Nicklaus, Donald P. Bottaro

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)943-951
Number of pages9
JournalJournal of medicinal chemistry
Volume52
Issue number4
DOIs
StatePublished - Feb 26 2009

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