Novel approaches to map small molecule-target interactions.

The quest for small molecule perturbators of protein function or a given cellular process lies at the heart of chemical biology and pharmaceutical research. Bioactive compounds need to be extensively characterized in the context of the modulated protein(s) or process(es) in living systems to unravel and confirm their mode of action. A crucial step in this workflow is the identification of the molecular targets for these small molecules, for which a generic methodology is lacking. Herein we summarize recently developed approaches for target identification spurred by advances in omics techniques and chemo- and bioinformatics analysis.

[1]  Michael M. Hann,et al.  RECAP-Retrosynthetic Combinatorial Analysis Procedure: A Powerful New Technique for Identifying Privileged Molecular Fragments with Useful Applications in Combinatorial Chemistry , 1998, J. Chem. Inf. Comput. Sci..

[2]  Jung-Hsin Lin,et al.  Target prediction of small molecules with information of key molecular interactions. , 2012, Current topics in medicinal chemistry.

[3]  L. Burdine,et al.  Target identification in chemical genetics: the (often) missing link. , 2004, Chemistry & biology.

[4]  Toshihiko Ogura,et al.  Identification of a Primary Target of Thalidomide Teratogenicity , 2010, Science.

[5]  J. Heitman,et al.  Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast , 1991, Science.

[6]  Nathan T. Ross,et al.  Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation , 2015, PloS one.

[7]  S. Kimura,et al.  Identification of a small-molecule inhibitor of DNA topoisomerase II by proteomic profiling. , 2011, Chemistry & biology.

[8]  G. Drewes,et al.  Tracking cancer drugs in living cells by thermal profiling of the proteome , 2014, Science.

[9]  F. Féru,et al.  Research Article: Selectivity‐determining Residues in Plk1 , 2007, Chemical biology & drug design.

[10]  Dennis B. Troup,et al.  NCBI GEO: mining tens of millions of expression profiles—database and tools update , 2006, Nucleic Acids Res..

[11]  Yanli Wang,et al.  Identifying Compound-Target Associations by Combining Bioactivity Profile Similarity Search and Public Databases Mining , 2011, J. Chem. Inf. Model..

[12]  M. Rosenfeld,et al.  Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens , 2014, Proceedings of the National Academy of Sciences.

[13]  H. Osada,et al.  Morphobase, an encyclopedic cell morphology database, and its use for drug target identification. , 2012, Chemistry & biology.

[14]  L Meijer,et al.  Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. , 1999, Cancer research.

[15]  Petra Schneider,et al.  Identifying the macromolecular targets of de novo-designed chemical entities through self-organizing map consensus , 2014, Proceedings of the National Academy of Sciences.

[16]  Qiang Zhou,et al.  RNA polymerase II elongation control. , 2012, Annual review of biochemistry.

[17]  P. Eyers,et al.  Discovery and Exploitation of Inhibitor-resistant Aurora and Polo Kinase Mutants for the Analysis of Mitotic Networks◆ , 2009, The Journal of Biological Chemistry.

[18]  Paul A Clemons,et al.  Complex phenotypic assays in high-throughput screening. , 2004, Current opinion in chemical biology.

[19]  Neil O Carragher,et al.  High-Content Phenotypic Profiling of Drug Response Signatures across Distinct Cancer Cells , 2010, Molecular Cancer Therapeutics.

[20]  S. Armstrong,et al.  Chromatin modifications as therapeutic targets in MLL-rearranged leukemia. , 2012, Trends in immunology.

[21]  J. Peters,et al.  The Small-Molecule Inhibitor BI 2536 Reveals Novel Insights into Mitotic Roles of Polo-like Kinase 1 , 2007, Current Biology.

[22]  B. Stockwell.  Chemical genetics: ligand-based discovery of gene function , 2000, Nature Reviews Genetics.

[23]  V. Keshamouni,et al.  Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition , 2010, Molecular Cancer Therapeutics.

[24]  Benito Munoz,et al.  Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics , 2015, Nature chemical biology.

[25]  M Ladetto,et al.  AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3β activation and RNA polymerase II inhibition , 2010, Oncogene.

[26]  H. Sprecher.  Metabolism of highly unsaturated n-3 and n-6 fatty acids. , 2000, Biochimica et biophysica acta.

[27]  Martin Serrano,et al.  Nucleic Acids Research Advance Access published October 18, 2007 ChemBank: a small-molecule screening and , 2007 .

[28]  G. Superti-Furga,et al.  Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death , 2015, ACS chemical biology.

[29]  P. Bork,et al.  Drug Target Identification Using Side-Effect Similarity , 2008, Science.

[30]  A. Fliri,et al.  Biological spectra analysis: Linking biological activity profiles to molecular structure. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  K. Chou,et al.  Predicting Drug-Target Interaction Networks Based on Functional Groups and Biological Features , 2010, PloS one.

[32]  D. Swinney,et al.  How were new medicines discovered? , 2011, Nature Reviews Drug Discovery.

[33]  Eric W. Klee,et al.  Genome-Wide Reverse Genetics Framework to Identify Novel Functions of the Vertebrate Secretome , 2006, PloS one.

[34]  James E. DiCarlo,et al.  RNA-Guided Human Genome Engineering via Cas9 , 2013, Science.

[35]  P. Arya,et al.  Advances in solution- and solid-phase synthesis toward the generation of natural product-like libraries. , 2009, Chemical reviews.

[36]  K. Shokat,et al.  Targeting the cancer kinome through polypharmacology , 2010, Nature Reviews Cancer.

[37]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[38]  Ruth Nussinov,et al.  Structure and dynamics of molecular networks: A novel paradigm of drug discovery. A comprehensive review , 2012, Pharmacology & therapeutics.

[39]  Di Chen,et al.  Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. , 2011, Current cancer drug targets.

[40]  B. Kuster,et al.  Mass spectrometry-based proteomics in preclinical drug discovery. , 2012, Chemistry & biology.

[41]  Yigong Shi,et al.  Birinapant (TL32711), a Bivalent SMAC Mimetic, Targets TRAF2-Associated cIAPs, Abrogates TNF-Induced NF-κB Activation, and Is Active in Patient-Derived Xenograft Models , 2014, Molecular Cancer Therapeutics.

[42]  G. Schneider,et al.  Repurposing de novo designed entities reveals phosphodiesterase 3B and cathepsin L modulators. , 2015, Chemical communications.

[43]  Xiaofeng S Zheng,et al.  Genetic and genomic approaches to identify and study the targets of bioactive small molecules. , 2004, Chemistry & biology.

[44]  R. Shoemaker.  The NCI60 human tumour cell line anticancer drug screen , 2006, Nature Reviews Cancer.

[45]  Elizabeth A. Winzeler,et al.  Genomic profiling of drug sensitivities via induced haploinsufficiency , 1999, Nature Genetics.

[46]  Jeffrey A. Porter,et al.  Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. , 2014, Nature chemical biology.

[47]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[48]  Jun O. Liu,et al.  XPB, a subunit of TFIIH, is a target of the natural product triptolide. , 2011, Nature chemical biology.

[49]  Markus Hartenfeller,et al.  DOGS: Reaction-Driven de novo Design of Bioactive Compounds , 2012, PLoS Comput. Biol..

[50]  J. O’Shea,et al.  Activation of human peripheral blood T lymphocytes by pharmacological induction of protein-tyrosine phosphorylation. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Lirong Wang,et al.  TargetHunter: An In Silico Target Identification Tool for Predicting Therapeutic Potential of Small Organic Molecules Based on Chemogenomic Database , 2013, The AAPS Journal.

[52]  William B. Smith,et al.  Genome-wide localization of small molecules , 2013, Nature Biotechnology.

[53]  Chee Keong Kwoh,et al.  Drug-target interaction prediction by learning from local information and neighbors , 2013, Bioinform..

[54]  Pingping Shen,et al.  TAB1: a target of triptolide in macrophages. , 2014, Chemistry & biology.

[55]  Lani F. Wu,et al.  Multidimensional Drug Profiling By Automated Microscopy , 2004, Science.

[56]  R. W. Davis,et al.  Targeted selection of recombinant clones through gene dosage effects. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Michael J. Keiser,et al.  Relating protein pharmacology by ligand chemistry , 2007, Nature Biotechnology.

[58]  Jürgen Bajorath,et al.  Identifying relationships between unrelated pharmaceutical target proteins on the basis of shared active compounds , 2017, Future science OA.

[59]  B. Stockwell.  Exploring biology with small organic molecules , 2004, Nature.

[60]  Herbert Waldmann,et al.  Target identification for small bioactive molecules: finding the needle in the haystack. , 2013, Angewandte Chemie.

[61]  B. Finzel,et al.  Inhibition of Mycobacterium tuberculosis Transaminase BioA by Aryl Hydrazines and Hydrazides , 2014, Chembiochem : a European journal of chemical biology.

[62]  Olivier Elemento,et al.  Using transcriptome sequencing to identify mechanisms of drug action and resistance , 2011, Nature chemical biology.

[63]  P. Nordlund,et al.  Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay , 2013, Science.

[64]  T. Corson,et al.  Triptolide Directly Inhibits dCTP Pyrophosphatase , 2011, Chembiochem : a European journal of chemical biology.

[65]  Michael J. Keiser,et al.  Large Scale Prediction and Testing of Drug Activity on Side-Effect Targets , 2012, Nature.

[66]  K. Shokat,et al.  Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases , 2008, Nature chemical biology.

[67]  S. Rees,et al.  Principles of early drug discovery , 2011, British journal of pharmacology.

[68]  Lei Xie,et al.  Structure-based systems biology for analyzing off-target binding. , 2011, Current opinion in structural biology.

[69]  John A. Tallarico,et al.  Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds , 2009, Nature Reviews Drug Discovery.

[70]  Inmar E. Givoni,et al.  Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast , 2006, Cell.

[71]  D. Bojanic,et al.  Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development. , 2005, Drug discovery today.

[72]  D. Nomura,et al.  Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis , 2010, Cell.

[73]  Petra Schneider,et al.  Self-organizing molecular fingerprints: a ligand-based view on drug-like chemical space and off-target prediction. , 2009, Future medicinal chemistry.

[74]  C. Stephan,et al.  Fatty acid binding proteins (FABPs) in prostate, bladder and kidney cancer cell lines and the use of IL-FABP as survival predictor in patients with renal cell carcinoma , 2011, BMC Cancer.

[75]  Yudong D. He,et al.  Functional Discovery via a Compendium of Expression Profiles , 2000, Cell.

[76]  Herbert Waldmann,et al.  (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. , 2015, Angewandte Chemie.

[77]  P. Clemons,et al.  NAMPT Is the Cellular Target of STF-31-Like Small-Molecule Probes , 2014, ACS chemical biology.

[78]  M. Fielden,et al.  Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action. , 2005, Journal of biotechnology.

[79]  Herbert Waldmann,et al.  Hide and seek: Identification and confirmation of small molecule protein targets. , 2015, Bioorganic & medicinal chemistry letters.

[80]  Mathias Frederiksen,et al.  FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p , 2015, Nature Communications.

[81]  Joshua A. Bittker,et al.  Correlating chemical sensitivity and basal gene expression reveals mechanism of action , 2015, Nature chemical biology.

[82]  D. Garrod,et al.  Pervanadate stabilizes desmosomes , 2008, Cell adhesion & migration.

[83]  Corey Nislow,et al.  A unique and universal molecular barcode array , 2006, Nature Methods.

[84]  R. Kennedy,et al.  PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFκB and PPARγ. , 2011, Cytokine.

[85]  K. Anderson,et al.  Analysis of mouse embryonic patterning and morphogenesis by forward genetics , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[86]  E. Degerman,et al.  Phosphorylation and activation of hormone-sensitive adipocyte phosphodiesterase type 3B. , 1998, Methods.

[87]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[88]  Bruce A. Posner,et al.  Improving drug discovery with high-content phenotypic screens by systematic selection of reporter cell lines , 2015, Nature Biotechnology.

[89]  D. Keppler,et al.  Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918 , 1999, British Journal of Cancer.

[90]  R. Tagliaferri,et al.  Discovery of drug mode of action and drug repositioning from transcriptional responses , 2010, Proceedings of the National Academy of Sciences.

[91]  Petra Schneider,et al.  Revealing the macromolecular targets of complex natural products. , 2014, Nature chemistry.

[92]  K D Paull,et al.  Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. , 1991, The Journal of biological chemistry.

[93]  Olivier Elemento,et al.  DrugTargetSeqR: a genomics- and CRISPR/Cas9-based method to analyze drug targets , 2014, Nature chemical biology.

[94]  David M. Rocke,et al.  Predicting ligand binding to proteins by affinity fingerprinting. , 1995, Chemistry & biology.

[95]  P. Nissen,et al.  Crystal structure of the high-affinity Na+,K+-ATPase–ouabain complex with Mg2+ bound in the cation binding site , 2013, Proceedings of the National Academy of Sciences.

[96]  B. Brinkley,et al.  Rotenone inhibition of spindle microtubule assembly in mammalian cells. , 1974, Experimental cell research.

[97]  Stefan Wetzel,et al.  Biology-oriented synthesis. , 2011, Angewandte Chemie.

[98]  N. Pryer,et al.  Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. , 2004, Molecular cancer therapeutics.

[99]  David A. Scott,et al.  Genome engineering using the CRISPR-Cas9 system , 2013, Nature Protocols.

[100]  John A. Tallarico,et al.  Integrating high-content screening and ligand-target prediction to identify mechanism of action. , 2008, Nature chemical biology.

[101]  Michael J. Keiser,et al.  Predicting new molecular targets for known drugs , 2009, Nature.

[102]  Makoto Muroi,et al.  Application of proteomic profiling based on 2D-DIGE for classification of compounds according to the mechanism of action. , 2010, Chemistry & biology.

[103]  David R Spring,et al.  Chemical genetics to chemical genomics: small molecules offer big insights. , 2005, Chemical Society reviews.

[104]  H. Schöler,et al.  Self-renewal of embryonic stem cells by a small molecule , 2006, Proceedings of the National Academy of Sciences.

[105]  G. Superti-Furga,et al.  Proteome-wide drug and metabolite interaction mapping by thermal-stability profiling , 2015, Nature Methods.

[106]  C. Bountra,et al.  Epigenetic protein families: a new frontier for drug discovery , 2012, Nature Reviews Drug Discovery.

[107]  G. Drewes,et al.  Thermal proteome profiling monitors ligand interactions with cellular membrane proteins , 2015, Nature Methods.

[108]  E. Lander,et al.  Identification of a selective small molecule inhibitor of breast cancer stem cells. , 2012, Bioorganic & medicinal chemistry letters.

[109]  A genome scale overexpression screen to reveal drug activity in human cells , 2014, Genome Medicine.

[110]  S. Robson,et al.  Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia , 2011, Nature.

[111]  M. Diccianni,et al.  3-amino thioacridone inhibits DNA synthesis and induce DNA damage in T-cell acute lymphoblastic leukemia (T-ALL) in a p16-dependent manner. , 2005, Journal of experimental therapeutics & oncology.

[112]  Makoto Muroi,et al.  Target identification of small molecules based on chemical biology approaches. , 2013, Molecular bioSystems.

[113]  S. Seité,et al.  Vemurafenib: an unusual UVA‐induced photosensitivity , 2013, Experimental dermatology.

[114]  Adrià Cereto-Massagué,et al.  Tools for in silico target fishing. , 2015, Methods.