Public resources for chemical probes: the journey so far and the road ahead.

High-quality small molecule chemical probes are extremely valuable for biological research and target validation. However, frequent use of flawed small-molecule inhibitors produces misleading results and diminishes the robustness of biomedical research. Several public resources are available to facilitate assessment and selection of better chemical probes for specific protein targets. Here, we review chemical probe resources, discuss their current strengths and limitations, and make recommendations for further improvements. Expert review resources provide in-depth analysis but currently cover only a limited portion of the liganded proteome. Computational resources encompass more proteins and are regularly updated, but have limitations in data availability and curation. We show how biomedical scientists may use these resources to choose the best available chemical probes for their research.

[1]  B. Al-Lazikani,et al.  Drugging cancer genomes , 2013, Nature Reviews Drug Discovery.

[2]  W. Kaelin,et al.  Common pitfalls in preclinical cancer target validation , 2017, Nature Reviews Cancer.

[3]  Yanli Wang,et al.  PubChem BioAssay: 2017 update , 2016, Nucleic Acids Res..

[4]  Paul Workman,et al.  canSAR: update to the cancer translational research and drug discovery knowledgebase , 2018, Nucleic Acids Res..

[5]  Tudor I. Oprea,et al.  A crowdsourcing evaluation of the NIH chemical probes. , 2009, Nature chemical biology.

[6]  Paul Workman,et al.  The pharmacological audit trail (PhAT): Use of tumor models to address critical issues in the preclinical development of targeted anticancer drugs , 2016 .

[7]  C. Crews,et al.  Targeted protein degradation: elements of PROTAC design. , 2019, Current opinion in chemical biology.

[8]  B. Cravatt,et al.  Determining target engagement in living systems. , 2013, Nature chemical biology.

[9]  Gautier Koscielny,et al.  Open Targets: a platform for therapeutic target identification and validation , 2016, Nucleic Acids Res..

[10]  William Lingran Chen,et al.  Chemoinformatics: Past, Present, and Future† , 2006, J. Chem. Inf. Model..

[11]  Jakob Felding,et al.  Open innovation platforms to boost pharmaceutical collaborations: evaluating external compounds for desired biological activity. , 2015, Future medicinal chemistry.

[12]  Eric Bender,et al.  Challenges: Crowdsourced solutions , 2016, Nature.

[13]  Jordi Mestres,et al.  Distant polypharmacology among MLP chemical probes. , 2015, ACS chemical biology.

[14]  Matthias Zwick,et al.  Target 2035: probing the human proteome. , 2019, Drug discovery today.

[15]  Wen Hwa Lee,et al.  Open Access Target Validation Is a More Efficient Way to Accelerate Drug Discovery , 2015, PLoS biology.

[16]  A. Lin,et al.  Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials , 2019, Science Translational Medicine.

[17]  Nathan Brown,et al.  Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor , 2018, Molecular oncology.

[18]  Albert A Antolin,et al.  Transforming cancer drug discovery with Big Data and AI , 2019, Expert opinion on drug discovery.

[19]  Monya Baker,et al.  Reproducibility: Check your chemistry , 2017, Nature.

[20]  Alasdair J. G. Gray,et al.  The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY , 2017, Nucleic Acids Res..

[21]  Emanuel J. V. Gonçalves,et al.  Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens , 2019, Nature.

[22]  Jürgen Bajorath,et al.  Computational Chemical Biology: Identification of Small Molecular Probes that Discriminate between Members of Target Protein Families , 2012, Chemical biology & drug design.

[23]  Anton Simeonov,et al.  Donated chemical probes for open science , 2018, eLife.

[24]  Paul Workman,et al.  Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases , 2019, bioRxiv.

[25]  Edward W. Tate,et al.  Validation and Invalidation of Chemical Probes for the Human N-myristoyltransferases , 2019, Cell chemical biology.

[26]  Florian Nigsch,et al.  Evidence-Based and Quantitative Prioritization of Tool Compounds in Phenotypic Drug Discovery. , 2016, Cell chemical biology.

[27]  A. Williamson Creating a structural genomics consortium , 2000, Nature Structural Biology.

[28]  T. Insel,et al.  NIH Molecular Libraries Initiative , 2004, Science.

[29]  Lyn H Jones,et al.  Cell permeable affinity- and activity-based probes. , 2015, Future medicinal chemistry.

[30]  Charles A Gersbach,et al.  Increasing the specificity of CRISPR systems with engineered RNA secondary structures , 2019, Nature Biotechnology.

[31]  John P. Overington,et al.  The promise and peril of chemical probes. , 2015, Nature chemical biology.

[32]  Ian Collins,et al.  Probing the Probes: Fitness Factors For Small Molecule Tools , 2010, Chemistry & biology.

[33]  Nancy Cheng,et al.  A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1 , 2015, Nature chemical biology.

[34]  George Papadatos,et al.  The ChEMBL database in 2017 , 2016, Nucleic Acids Res..

[35]  Jian Jin,et al.  Report and Application of a Tool Compound Data Set , 2017, J. Chem. Inf. Model..

[36]  Tudor I. Oprea,et al.  Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes , 2015, Cell.

[37]  Mark E Bunnage,et al.  Target validation using chemical probes. , 2013, Nature chemical biology.

[38]  Andrew R. Scott Chemical probes: A shared toolbox , 2016, Nature.

[39]  Y. Reiss,et al.  The E3 Ubiquitin-Ligase Bmi1/Ring1A Controls the Proteasomal Degradation of Top2α Cleavage Complex – A Potentially New Drug Target , 2009, PloS one.

[40]  Susanne Müller,et al.  Open access chemical probes for epigenetic targets , 2015, Future medicinal chemistry.

[41]  X Chen,et al.  BindingDB: a web-accessible molecular recognition database. , 2001, Combinatorial chemistry & high throughput screening.

[42]  Asher Mullard Boehringer Ingelheim experiments with open-access chemical probes , 2017, Nature Reviews Drug Discovery.

[43]  Daniel Svozil,et al.  Probes &Drugs portal: an interactive, open data resource for chemical biology , 2017, Nature Methods.

[44]  Jürgen Bajorath,et al.  Extracting Compound Profiling Matrices from Screening Data , 2018, ACS omega.

[45]  Alessio Ciulli,et al.  Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology , 2016, Future medicinal chemistry.

[46]  Ian Collins,et al.  Objective, Quantitative, Data-Driven Assessment of Chemical Probes , 2017, bioRxiv.

[47]  Asher Mullard,et al.  A probe for every protein , 2019, Nature Reviews Drug Discovery.

[48]  Alejandro Aguayo-Orozco,et al.  A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity. , 2019, Journal of medicinal chemistry.

[49]  A. Valencia,et al.  Information Retrieval and Text Mining Technologies for Chemistry. , 2017, Chemical reviews.

[50]  Stephen V Frye,et al.  The art of the chemical probe. , 2010, Nature chemical biology.

[51]  Shili Duan,et al.  A chemical toolbox for the study of bromodomains and epigenetic signaling , 2018, bioRxiv.

[52]  James R. Brown,et al.  Thousands of chemical starting points for antimalarial lead identification , 2010, Nature.

[53]  Jian Jin,et al.  A chemical biology toolbox to study protein methyltransferases and epigenetic signaling , 2019, Nature Communications.

[54]  Paul Workman,et al.  Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer , 2019, Oncogene.

[55]  William B. Smith,et al.  Selective inhibition of BET bromodomains , 2010, Nature.

[56]  Johann S. de Bono,et al.  Appraising iniparib, the PARP inhibitor that never was—what must we learn? , 2013, Nature Reviews Clinical Oncology.

[57]  Julian Blagg,et al.  Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology , 2017, Cancer cell.

[58]  Mario Medvedovic,et al.  Cheminformatics Tools for Analyzing and Designing Optimized Small-Molecule Collections and Libraries. , 2019, Cell chemical biology.