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Cell. 2015 Jun 4;161(6):1252-65. doi: 10.1016/j.cell.2015.05.023.

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.

Author information

1
Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: stuart_schreiber@harvard.edu.
2
Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: jkotz@broadinstitute.org.
3
Johns Hopkins School of Medicine Ion Channel Center, Baltimore, MD 21205, USA.
4
University of Kansas Specialized Chemistry Center, Lawrence, KS 66045, USA; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 66045, USA.
5
NIH Chemical Genomics Center, National Institutes of Health, Rockville, MD 20850, USA; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
6
Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, and Lake Nona, FL 32827, USA.
7
Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, and Jupiter, FL 33458, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
8
Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
9
University of New Mexico Center for Molecular Discovery, Albuquerque, NM 87131, USA; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
10
The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
11
Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
12
Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
13
Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
14
Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
15
University of Kansas Specialized Chemistry Center, Lawrence, KS 66045, USA.
16
Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, and Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, 33458, USA.
17
Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, and Jupiter, FL 33458, USA.
18
Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, and Jupiter, FL 33458, USA; Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA.
19
University of New Mexico Center for Molecular Discovery, Albuquerque, NM 87131, USA; Department of Internal Medicine, University of New Mexico, Albuquerque, NM, 87131, USA.
20
The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Abstract

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery.

PMID:
26046436
PMCID:
PMC4564295
DOI:
10.1016/j.cell.2015.05.023
[Indexed for MEDLINE]
Free PMC Article

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