Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Stuart L Schreiber; Joanne D Kotz; Min Li; Jeffrey Aubé; Christopher P Austin; John C Reed; Hugh Rosen; E Lucile White; Larry A Sklar; Craig W Lindsley; Benjamin R Alexander; Joshua A Bittker; Paul A Clemons; Andrea de Souza; Michael A Foley; Michelle Palmer; Alykhan F Shamji; Mathias J Wawer; Owen McManus; Meng Wu; Beiyan Zou; Haibo Yu; Jennifer E Golden; Frank J Schoenen; Anton Simeonov; Ajit Jadhav; Michael R Jackson; Anthony B Pinkerton; Thomas D Y Chung; Patrick R Griffin; Benjamin F Cravatt; Peter S Hodder; William R Roush; Edward Roberts; Dong-Hoon Chung; Colleen B Jonsson; James W Noah; William E Severson; Subramaniam Ananthan; Bruce Edwards; Tudor I Oprea; P Jeffrey Conn; Corey R Hopkins; Michael R Wood; Shaun R Stauffer; Kyle A Emmitte; NIH Molecular Libraries Project Team

doi:10.1016/j.cell.2015.05.023

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

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

Authors

Stuart L Schreiber¹, Joanne D Kotz², Min Li³, Jeffrey Aubé⁴, Christopher P Austin⁵, John C Reed⁶, Hugh Rosen⁷, E Lucile White⁸, Larry A Sklar⁹, Craig W Lindsley¹⁰, Benjamin R Alexander¹¹, Joshua A Bittker¹², Paul A Clemons¹³, Andrea de Souza¹⁴, Michael A Foley¹⁴, Michelle Palmer¹⁴, Alykhan F Shamji¹³, Mathias J Wawer¹³, Owen McManus³, Meng Wu³, Beiyan Zou³, Haibo Yu³, Jennifer E Golden¹⁵, Frank J Schoenen¹⁵, Anton Simeonov⁵, Ajit Jadhav⁵, Michael R Jackson⁶, Anthony B Pinkerton⁶, Thomas D Y Chung⁶, Patrick R Griffin¹⁶, Benjamin F Cravatt⁷, Peter S Hodder¹⁷, William R Roush¹⁸, Edward Roberts¹⁷, Dong-Hoon Chung⁸, Colleen B Jonsson⁸, James W Noah⁸, William E Severson⁸, Subramaniam Ananthan⁸, Bruce Edwards⁹, Tudor I Oprea¹⁹, P Jeffrey Conn¹⁰, Corey R Hopkins¹⁰, Michael R Wood¹⁰, Shaun R Stauffer²⁰, Kyle A Emmitte¹⁰; NIH Molecular Libraries Project Team

Collaborators

NIH Molecular Libraries Project Team:
Linda S Brady, Jamie Driscoll, Ingrid Y Li, Carson R Loomis, Ronald N Margolis, Enrique Michelotti, Mary E Perry, Ajay Pillai, Yong Yao

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Animals
Drug Discovery*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
High-Throughput Screening Assays
Humans
National Institutes of Health (U.S.)
Small Molecule Libraries*
United States

Substances

Enzyme Inhibitors
Small Molecule Libraries

Abstract

Publication types

MeSH terms

Substances

Grants and funding