title: Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.
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.
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: 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.
authors.forename: Joanne D
authors.initials: JD
authors.lastname: Kotz
authors.affiliation: Johns Hopkins School of Medicine Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66045, USA; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 66045, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: NIH Chemical Genomics Center, National Institutes of Health, Rockville, MD 20850, USA; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, and Lake Nona, FL 32827, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: 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.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: E Lucile
authors.initials: EL
authors.lastname: White
authors.affiliation: 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.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.affiliation: 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.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: 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.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Alexander
authors.affiliation: 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.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.affiliation: 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.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: de Souza
authors.affiliation: Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.affiliation: Probe Development Center, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Palmer
authors.affiliation: 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.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: 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.
authors.forename: Mathias J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Johns Hopkins School of Medicine Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Owen
authors.initials: O
authors.lastname: McManus
authors.affiliation: Johns Hopkins School of Medicine Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Johns Hopkins School of Medicine Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zou
authors.affiliation: Johns Hopkins School of Medicine Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66045, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66045, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.affiliation: NIH Chemical Genomics Center, National Institutes of Health, Rockville, MD 20850, USA; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: NIH Chemical Genomics Center, National Institutes of Health, Rockville, MD 20850, USA; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, and Lake Nona, FL 32827, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jackson
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, and Lake Nona, FL 32827, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, and Lake Nona, FL 32827, USA.
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: 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.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, and Jupiter, FL 33458, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.affiliation: 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.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, and Jupiter, FL 33458, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.affiliation: Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Chung
authors.affiliation: Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Colleen B
authors.initials: CB
authors.lastname: Jonsson
authors.affiliation: Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Noah
authors.affiliation: Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Severson
authors.affiliation: Southern Research Specialized Biocontainment Screening Center, Southern Research Institute, Birmingham, AL 35205, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.affiliation: 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.
authors.forename: Bruce
authors.initials: B
authors.lastname: Edwards
authors.affiliation: University of New Mexico Center for Molecular Discovery, Albuquerque, NM 87131, USA; Department of Internal Medicine, University of New Mexico, Albuquerque, NM, 87131, USA.
authors.forename: Tudor I
authors.initials: TI
authors.lastname: Oprea
authors.affiliation: 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.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: 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.
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.affiliation: 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.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: 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.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D009316:National Institutes of Health (U.S.); D054852:Small Molecule Libraries; D014481:United States
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries