Michael Wei, MD, PhD

Publication Details

  • Next-Generation NAMPT Inhibitors Identified by Sequential High-Throughput Phenotypic Chemical and Functional Genomic Screens. Chemistry & biology Matheny, C. J., Wei, M. C., Bassik, M. C., Donnelly, A. J., Kampmann, M., Iwasaki, M., Piloto, O., Solow-Cordero, D. E., Bouley, D. M., Rau, R., Brown, P., McManus, M. T., Weissman, J. S., Cleary, M. L. 2013; 20 (11): 1352-1363

    Abstract:

    Phenotypic high-throughput chemical screens allow for discovery of small molecules that modulate complex phenotypes and provide lead compounds for novel therapies; however, identification of the mechanistically relevant targets remains a major experimental challenge. We report the application of sequential unbiased high-throughput chemical and ultracomplex small hairpin RNA (shRNA) screens to identify a distinctive class of inhibitors that target nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide, a crucial cofactor in many biochemical processes. The lead compound STF-118804 is a highly specific NAMPT inhibitor, improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells. Tandem high-throughput screening using chemical and ultracomplex shRNA libraries, therefore, provides a rapid chemical genetics approach for seamless progression from small-molecule lead identification to target discovery and validation.

    View details for DOI 10.1016/j.chembiol.2013.09.014

    View details for PubMedID 24183972

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