Biomedical researchers in the 21st century work in the epicenter of an explosion in the understanding of human disease. The complete sequences of relevant genomes, like the human and various infectious organisms, lay the foundation for the next steps in probing molecular mechanisms of disease. Broad Institute researchers recognized at an early stage of this revolution that the perturbation of the cellular pathways that underlie phenotypic changes with small molecules will make it possible to dissect cell circuitry and disease biology, thus enabling a path forward to correcting human diseases. We have operated a Screening Facility in a production mode over the past ten years in an open data-sharing environment, created the first comprehensive and public small-molecule database and analysis environment containing over 20 million binding and assay-well measurements, a novel chemical biology information model and many powerful analysis tools, and, in 2007, made a substantial investment in personnel, screening automation, LIMS and robotics that has substantially increased these already significant production capabilities. This screening facility resides within a rich environment focused on small molecules and small-molecule screening integrated with disease biology and genome biology. We propose here a plan to operate a Comprehensive Screening Center at the Broad Institute of Harvard and MIT (BCSC), leveraging and complementing existing organizational and infrastructure initiatives by collaborating with a wider MLPCN research community.

Public Health Relevance

Impact on human health The proposed Comprehensive Screening Center will generate many small-molecule probes of human disease, including but not limited to cancer, schizophrenia, malaria, tuberculosis, and diabetes. The probes are outstanding starting points for the development of novel therapeutics. The Center will also provide early stage optimization of the probes so as to understand their potential for treatment and to increase the probability that they can lead to safe and effective therapeutics in the future. All data will be made publicly available, which will enable more therapeutic discovery efforts than would be possible otherwise.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRG1-IFCN-K (52))
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Schloss, Jeffery
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Broad Institute, Inc.
United States
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Sharabi, Kfir; Lin, Hua; Tavares, Clint D J et al. (2017) Selective Chemical Inhibition of PGC-1? Gluconeogenic Activity Ameliorates Type 2 Diabetes. Cell 169:148-160.e15
Wagner, Florence F; Bishop, Joshua A; Gale, Jennifer P et al. (2016) Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects. ACS Chem Biol 11:1952-63
Zielonka, Jacek; Zielonka, Monika; VerPlank, Lynn et al. (2016) Mitigation of NADPH Oxidase 2 Activity as a Strategy to Inhibit Peroxynitrite Formation. J Biol Chem 291:7029-44
de Waal, Luc; Lewis, Timothy A; Rees, Matthew G et al. (2016) Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics. Nat Chem Biol 12:102-8
Lessing, Derek; Dial, Thomas O; Wei, Chunyao et al. (2016) A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation. Proc Natl Acad Sci U S A 113:14366-14371
Bageshwar, Umesh K; VerPlank, Lynn; Baker, Dwight et al. (2016) High Throughput Screen for Escherichia coli Twin Arginine Translocation (Tat) Inhibitors. PLoS One 11:e0149659
Lopez-Sambrooks, Cecilia; Shrimal, Shiteshu; Khodier, Carol et al. (2016) Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nat Chem Biol 12:1023-1030
Sykes, David B; Kfoury, Youmna S; Mercier, Fran├žois E et al. (2016) Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 167:171-186.e15
Bekendam, Roelof H; Bendapudi, Pavan K; Lin, Lin et al. (2016) A substrate-driven allosteric switch that enhances PDI catalytic activity. Nat Commun 7:12579
Lukens, Amanda K; Heidebrecht Jr, Richard W; Mulrooney, Carol et al. (2015) Diversity-oriented synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors. J Infect Dis 211:1097-103

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