The promise and peril of chemical probes

Cheryl H Arrowsmith¹, James E Audia², Christopher Austin³, Jonathan Baell⁴, Jonathan Bennett⁵, Julian Blagg⁶, Chas Bountra⁷, Paul E Brennan⁸, Peter J Brown⁹, Mark E Bunnage¹⁰, Carolyn Buser-Doepner¹¹, Robert M Campbell¹², Adrian J Carter¹³, Philip Cohen¹⁴, Robert A Copeland¹⁵, Ben Cravatt¹⁶, Jayme L Dahlin¹⁷, Dashyant Dhanak¹⁸, Aled M Edwards⁹, Mathias Frederiksen¹⁹, Stephen V Frye²⁰, Nathanael Gray²¹, Charles E Grimshaw²², David Hepworth¹⁰, Trevor Howe²³, Kilian V M Huber²⁴, Jian Jin²⁵, Stefan Knapp⁸, Joanne D Kotz²⁶, Ryan G Kruger²⁷, Derek Lowe²⁸, Mary M Mader¹², Brian Marsden⁷, Anke Mueller-Fahrnow²⁹, Susanne Müller⁸, Ronan C O'Hagan³⁰, John P Overington³¹, Dafydd R Owen¹⁰, Saul H Rosenberg³², Bryan Roth³³, Ruth Ross³⁴, Matthieu Schapira³⁵, Stuart L Schreiber²⁶, Brian Shoichet³⁶, Michael Sundström³⁷, Giulio Superti-Furga³⁸, Jack Taunton³⁹, Leticia Toledo-Sherman⁴⁰, Chris Walpole⁴¹, Michael A Walters⁴², Timothy M Willson⁴³, Paul Workman⁶, Robert N Young⁴⁴, William J Zuercher⁴³

Affiliations

¹ 1] Structural Genomics Consortium, Toronto, Ontario, Canada. [2] Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
² Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
³ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia.
⁵ Discovery Chemistry, Merck Research Laboratories, Boston, Massachusetts, USA.
⁶ Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
⁷ Structural Genomics Consortium, University of Oxford, Oxford, UK.
⁸ 1] Structural Genomics Consortium, University of Oxford, Oxford, UK. [2] Target Discovery Institute, University of Oxford, Oxford, UK.
⁹ Structural Genomics Consortium, Toronto, Ontario, Canada.
¹⁰ Worldwide Medicinal Chemistry, Pfizer, Cambridge, Massachusetts, USA.
¹¹ GlaxoSmithKline, Collegeville, Pennsylvania, USA.
¹² Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
¹³ Corporate Department Research Networking, Boehringer Ingelheim GmbH, Ingelheim, Germany.
¹⁴ The Sir James Black Centre, University of Dundee, Dundee, UK.
¹⁵ Epizyme, Inc., Cambridge, Massachusetts, USA.
¹⁶ Department of Chemical Physiology, Scripps Research Institute, San Diego, California, USA.
¹⁷ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
¹⁸ Janssen Research and Development, Spring House, Pennsylvania, USA.
¹⁹ Novartis Institutes for BioMedical Research, Novartis, Basel, Switzerland.
²⁰ Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard University, Cambridge, Massachusetts, USA.
²² Takeda California Inc., San Diego, California, USA.
²³ Janssen Research and Development, High Wycombe, Bucks, UK.
²⁴ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
²⁵ 1] Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁶ Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
²⁷ Cancer Epigenetics, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
²⁸ Vertex Pharmaceuticals, Boston, Massachusetts, USA.
²⁹ Bayer Pharma AG, Berlin, Germany.
³⁰ Oncology Discovery, Merck Research Laboratories, Boston, Massachusetts, USA.
³¹ 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Stratified Medical, London, UK.
³² AbbVie, North Chicago, Illinois, USA.
³³ The National Institute of Mental Health Psychoactive Active Drug Screening Program (NIMH PDSP), Department of Pharmacology, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
³⁴ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³⁵ 1] Structural Genomics Consortium, Toronto, Ontario, Canada. [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³⁶ School of Pharmacy, University of California-San Francisco, San Francisco, California, USA.
³⁷ 1] Structural Genomics Consortium, Karolinska Institutet, Solna, Sweden. [2] Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Solna, Sweden.
³⁸ 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [2] Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
³⁹ 1] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA. [2] Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, California, USA.
⁴⁰ CHDI Management/CHDI Foundation, Los Angeles, California, USA.
⁴¹ Structural Genomics Consortium, McGill University, Montreal, Quebec, Canada.
⁴² University of Minnesota, Minneapolis, Minnesota, USA.
⁴³ 1] UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Structural Genomics Consortium, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴⁴ Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.

PMID: 26196764
PMCID: PMC4706458
DOI: 10.1038/nchembio.1867

The promise and peril of chemical probes

Cheryl H Arrowsmith et al. Nat Chem Biol. 2015 Aug.

. 2015 Aug;11(8):536-41.

doi: 10.1038/nchembio.1867.

Authors

Affiliations

¹ 1] Structural Genomics Consortium, Toronto, Ontario, Canada. [2] Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
² Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
³ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia.
⁵ Discovery Chemistry, Merck Research Laboratories, Boston, Massachusetts, USA.
⁶ Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
⁷ Structural Genomics Consortium, University of Oxford, Oxford, UK.
⁸ 1] Structural Genomics Consortium, University of Oxford, Oxford, UK. [2] Target Discovery Institute, University of Oxford, Oxford, UK.
⁹ Structural Genomics Consortium, Toronto, Ontario, Canada.
¹⁰ Worldwide Medicinal Chemistry, Pfizer, Cambridge, Massachusetts, USA.
¹¹ GlaxoSmithKline, Collegeville, Pennsylvania, USA.
¹² Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.
¹³ Corporate Department Research Networking, Boehringer Ingelheim GmbH, Ingelheim, Germany.
¹⁴ The Sir James Black Centre, University of Dundee, Dundee, UK.
¹⁵ Epizyme, Inc., Cambridge, Massachusetts, USA.
¹⁶ Department of Chemical Physiology, Scripps Research Institute, San Diego, California, USA.
¹⁷ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
¹⁸ Janssen Research and Development, Spring House, Pennsylvania, USA.
¹⁹ Novartis Institutes for BioMedical Research, Novartis, Basel, Switzerland.
²⁰ Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
²¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard University, Cambridge, Massachusetts, USA.
²² Takeda California Inc., San Diego, California, USA.
²³ Janssen Research and Development, High Wycombe, Bucks, UK.
²⁴ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
²⁵ 1] Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁶ Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
²⁷ Cancer Epigenetics, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
²⁸ Vertex Pharmaceuticals, Boston, Massachusetts, USA.
²⁹ Bayer Pharma AG, Berlin, Germany.
³⁰ Oncology Discovery, Merck Research Laboratories, Boston, Massachusetts, USA.
³¹ 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Stratified Medical, London, UK.
³² AbbVie, North Chicago, Illinois, USA.
³³ The National Institute of Mental Health Psychoactive Active Drug Screening Program (NIMH PDSP), Department of Pharmacology, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
³⁴ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³⁵ 1] Structural Genomics Consortium, Toronto, Ontario, Canada. [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³⁶ School of Pharmacy, University of California-San Francisco, San Francisco, California, USA.
³⁷ 1] Structural Genomics Consortium, Karolinska Institutet, Solna, Sweden. [2] Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Solna, Sweden.
³⁸ 1] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [2] Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
³⁹ 1] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA. [2] Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, California, USA.
⁴⁰ CHDI Management/CHDI Foundation, Los Angeles, California, USA.
⁴¹ Structural Genomics Consortium, McGill University, Montreal, Quebec, Canada.
⁴² University of Minnesota, Minneapolis, Minnesota, USA.
⁴³ 1] UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Structural Genomics Consortium, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴⁴ Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.

PMID: 26196764
PMCID: PMC4706458
DOI: 10.1038/nchembio.1867

Erratum in

Nat Chem Biol. 2015 Aug;11(8):541. Roth, Brian [Corrected to Roth, Bryan] and Frederiksen, Mathias [Added]
Corrigendum: The promise and peril of chemical probes.
Arrowsmith CH, Audia JE, Austin C, Baell J, Bennett J, Blagg J, Bountra C, Brennan PE, Brown PJ, Bunnage ME, Buser-Doepner C, Campbell RM, Carter AJ, Cohen P, Copeland RA, Cravatt B, Dahlin JL, Dhanak D, Edwards AM, Frederiksen M, Frye SV, Gray N, Grimshaw CE, Hepworth D, Howe T, Huber KV, Jin J, Knapp S, Kotz JD, Kruger RG, Lowe D, Mader MM, Marsden B, Mueller-Fahrnow A, Müller S, O'Hagan RC, Overington JP, Owen DR, Rosenberg SH, Ross R, Roth B, Schapira M, Schreiber SL, Shoichet B, Sundström M, Superti-Furga G, Taunton J, Toledo-Sherman L, Walpole C, Walters MA, Willson TM, Workman P, Young RN, Zuercher WJ. Arrowsmith CH, et al. Nat Chem Biol. 2015 Nov;11(11):887. doi: 10.1038/nchembio1115-887c. Nat Chem Biol. 2015. PMID: 26485080 No abstract available.

Abstract

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

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Figures

**Figure 1**
Different purposes and requirements for chemical probes and drugs. IP, intellectual property; MoA, mechanism of action; MW, molecular weight.

**Figure 2**
Chemical probes are valuable research tools. (a) Open access to quality chemical probes can inform initial target selection. (b,c) Examples of chemical probes for the LXRs (b) and BET family bromodomains (c).

**Figure 3**
Structures for selected compounds.

See this image and copyright information in PMC

References

1. Martinez Molina D, et al. Science. 2013;341:84–87. - PubMed
1. Thirumurugan P, Matosiuk D, Jozwiak K. Chem Rev. 2013;113:4905–4979. - PubMed
1. Baell J, Walters MA. Nature. 2014;513:481–483. - PubMed
1. Bunnage ME, Chekler EL, Jones LH. Nat Chem Biol. 2013;9:195–199. - PubMed
1. Frye SV. Nat Chem Biol. 2010;6:159–161. - PubMed

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The promise and peril of chemical probes

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The promise and peril of chemical probes

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