2-[[[2-methyl-1-(phenylmethyl)-5-benzimidazolyl]amino]methyl]phenol and Breast-Neoplasms

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.

Topics: Amino Acid Sequence; Aniline Compounds; Antineoplastic Agents; Binding Sites; Breast Neoplasms; Catalytic Domain; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, 3-Ring; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Piperazines; Pyrimidines; Quantitative Structure-Activity Relationship; Quinazolines; Quinolines; Receptor, ErbB-2; Small Molecule Libraries