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.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HG005032-05
Application #
8336972
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (52))
Program Officer
Schloss, Jeffery
Project Start
2008-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$15,462,500
Indirect Cost
$292,851
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Comer, Eamon; Beaudoin, Jennifer A; Kato, Nobutaka et al. (2014) Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents. J Med Chem 57:8496-502
Wurst, Jacqueline M; Drake, Eric J; Theriault, Jimmy R et al. (2014) Identification of inhibitors of PvdQ, an enzyme involved in the synthesis of the siderophore pyoverdine. ACS Chem Biol 9:1536-44
Wawer, Mathias J; Li, Kejie; Gustafsdottir, Sigrun M et al. (2014) Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling. Proc Natl Acad Sci U S A 111:10911-6
Hu, Longqin; Magesh, Sadagopan; Chen, Lin et al. (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 23:3039-43
Ljosa, Vebjorn; Caie, Peter D; Ter Horst, Rob et al. (2013) Comparison of methods for image-based profiling of cellular morphological responses to small-molecule treatment. J Biomol Screen 18:1321-9
Mulrooney, Carol A; Lahr, David L; Quintin, Michael J et al. (2013) An informatic pipeline for managing high-throughput screening experiments and analyzing data from stereochemically diverse libraries. J Comput Aided Mol Des 27:455-68
Germain, Andrew R; Carmody, Leigh C; Nag, Partha P et al. (2013) Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells. Bioorg Med Chem Lett 23:1834-8
Youngsaye, Willmen; Dockendorff, Chris; Vincent, Benjamin et al. (2012) Overcoming fluconazole resistance in Candida albicans clinical isolates with tetracyclic indoles. Bioorg Med Chem Lett 22:3362-5
Weiwer, Michel; Bittker, Joshua A; Lewis, Timothy A et al. (2012) Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 22:1822-6
Swamidass, S Joshua; Calhoun, Bradley T; Bittker, Joshua A et al. (2012) Utility-aware screening with clique-oriented prioritization. J Chem Inf Model 52:29-37

Showing the most recent 10 out of 21 publications