J. Med. Chem. 2008, 51, 3367–3377
3367
Discovery of Novel Small-Molecule Inhibitors of Human Epidermal Growth Factor Receptor-2: Combined Ligand and Target-Based Approach Rambabu Gundla,† Roza Kazemi,† Ramadevi Sanam,‡ Ravikumar Muttineni,‡ Jagarlapudi A. R. P. Sarma,‡ Raveendra Dayam,† and Nouri Neamati*,† Department of Pharmacology and Pharmaceutical Sciences, UniVersity of Southern California, School of Pharmacy, 1985 Zonal AVenue, Los Angeles, California, DiVision of Informatics, GVK Biosciences PVt. Ltd., Technocrats Industrial Estate, Balanagar, Hyderabad, Andhra Pradesh, India ReceiVed NoVember 5, 2007
Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values
