Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and target-based approach.
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Gundla R, Kazemi R, Sanam R, Muttineni R, Sarma JA, Dayam R, Neamati N
Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and target-based approach.
J Med Chem. 2008 Jun 26;51(12):3367-77. doi: 10.1021/jm7013875.
- PubMed ID
- 18500794 [ View in PubMed]
- Abstract
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 <10 microM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Lapatinib Receptor tyrosine-protein kinase erbB-2 IC 50 (nM) 9 N/A N/A Details