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ID: ALA4602694
Journal: J Med Chem
Title: Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein.
Authors: Lin CY, Wu HY, Hsu YL, Cheng TR, Liu JH, Huang RJ, Hsiao TH, Wang CJ, Hung PF, Lan A, Pan SH, Chein RJ, Wong CH, Yang PC.
Abstract: Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.
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