The discovery and mechanism of action of novel tumor-selective and apoptosis-inducing 3,5-diaryl-1,2,4-oxadiazole series using a chemical genetics approach

摘要: A novel series of 3,5-diaryl-oxadiazoles was identified as apoptosis-inducing agents through our cell and chemical genetics–based screening assay for compounds that induce apoptosis using a genetics approach. Several analogues from this including MX-74420 MX-126374 were further characterized. MX-126374, lead compound series, shown to inhibit growth selectively in tumor cells. To elucidate the mechanism(s) by which class alters signal transduction pathway ultimately leads apoptosis, expression profiling Affymetrix Gene Chip array technology done along with other molecular biochemical analyses. Interestingly, we have several key genes (cyclin D1, transforming factor-B1, p21, insulin-like factor-BP3) are altered presence compound, leading characterization activation apoptosis. also showed significant inhibition single agent combination paclitaxel murine models. Using photoaffinity labeling, tail-interacting protein 47, an factor-II receptor binding protein, target. Further studies indicated down-regulation 47 cancer cells small interfering RNA shows similar profile treatment. These data suggest may be new anticancer drugs tumor-selective support discovery drug targets genetic approaches. [Mol Cancer Ther 2005;4(5):761–71]