Review

. 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

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, Affiliations

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.

PMID: 26046436
PMCID: PMC4564295
DOI: 10.1016/j.cell.2015.05.023

Review

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Stuart L Schreiber et al. Cell. 2015.

. 2015 Jun 4;161(6):1252-65.

doi: 10.1016/j.cell.2015.05.023.

Authors

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.

PMID: 26046436
PMCID: PMC4564295
DOI: 10.1016/j.cell.2015.05.023

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.

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Figures

**Fig. 1. Centers comprising the MLPCN Network**

**Fig. 2. Spectrum of targets modulated by MLP probes**
Target classes modulated by MLP probes are visualized based on HTS data and user-defined thresholds. Arc lengths represent the number of distinct targets within a target class that are modulated by this collection of probes. This graph was generated using the BioAssay Research Database (BARD; bard.nih.gov), which was generated by the MLP to enable users to mine and visualize small-molecule activity data. The graph depicts the bioactivity of about 65% of the total number of MLP probes across 415 unique assays associated with 460 targets, which were categorized using the Panther database into 110 protein categories. The breadth of target classes highlights the diverse biology and target space explored by the MLP.

**Fig. 3. MLP probes highlighted in vignettes**

See this image and copyright information in PMC

References

1. Adibekian A, Martin BR, Chang JW, Hsu KL, Tsuboi K, Bachovchin DA, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Hodder PS, Rosen H, Cravatt BF. Confirming target engagement for reversible inhibitors in vivo by kinetically tuned activity-based probes. J Am Chem Soc. 2012;134:10345–10348. - PMC - PubMed
1. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Vander Heiden MG. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012;8:839–847. - PMC - PubMed
1. Arrowsmith J. Trial watch: Phase II failures: 2008–2010. Nat Rev Drug Discov. 2011a;10:328–329. - PubMed
1. Arrowsmith J. Trial watch: phase III and submission failures, 2007–2010. Nat Rev Drug Discov. 2011b;10:87. - PubMed
1. Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010;12:716–721. - PubMed

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Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Collaborators

Affiliations

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources