TY - JOUR
T1 - Next-generation NAMPT inhibitors identified by sequential high-throughput phenotypic chemical and functional genomic screens
AU - Matheny, Christina J.
AU - Wei, Michael C.
AU - Bassik, Michael C.
AU - Donnelly, Alicia J.
AU - Kampmann, Martin
AU - Iwasaki, Masayuki
AU - Piloto, Obdulio
AU - Solow-Cordero, David E.
AU - Bouley, Donna M.
AU - Rau, Rachel
AU - Brown, Patrick
AU - McManus, Michael T.
AU - Weissman, Jonathan S.
AU - Cleary, Michael L.
N1 - Funding Information:
We thank K. Grimes, D. Mochly-Rosen, and advisors of the SPARK Translational Research Program at Stanford for their support and guidance. We acknowledge the advice and services of the Shared FACS Facility, Transgenic Research Center, Small Animal Imaging Facility, and High-Throughput Bioscience Center. We thank L. Alexandrova and the Stanford Mass Spectrometry Facility for pharmacokinetic analysis, S. Lynch for NMR analysis, and N. Cyr for graphical assistance. These studies were supported by funds from the National Institutes of Health (NIH; Clinical and Translational Science awards UL1-RR02744 and UL1-TR000093, Tumor Biology Training grant T32-009151, and 1U01CA168370-01 [to J.S.W. and M.T.M.]; and grant R01 GM80783 [to M.T.M.]), the Lucile Packard Foundation for Children’s Health, the SPARK Translational Research Program at Stanford, the Leukemia and Lymphoma Society (to M.L.C.), the St. Baldrick’s Foundation (to M.C.W.), a Howard Hughes Collaborative Initiative Award (to J.S.W.), and the University of California, San Francisco Program for Breakthrough Biomedical Research (to J.S.W. and M.T.M.).
PY - 2013/11/21
Y1 - 2013/11/21
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chembiol.2013.09.014
DO - 10.1016/j.chembiol.2013.09.014
M3 - Article
C2 - 24183972
AN - SCOPUS:84888262057
SN - 1074-5521
VL - 20
SP - 1352
EP - 1363
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 11
ER -