Cell permeable affinity- and activity-based probes.

Chemical biology has a significant role to play in the discovery and validation of new therapeutic targets. Activity- and affinity-based probes have demonstrated considerable promise in the drug discovery setting as they provide a chemoproteomic means to confirm and quantify target engagement and selectivity of small molecule drug candidates. Many of these technologies have been developed using cell lysate (through the use of resin-immobilized enzyme inhibitors for example), but this does not represent the biology of an intact cell. This review highlights recent advances made in the design and application of cell-permeable probes that report on target activity and drug-target occupancy in living cells, thus providing a means to decipher molecular pharmacology and pathology in a more physiologically relevant manner.

[1]  Dustin J Maly,et al.  Affinity-based probes based on type II kinase inhibitors. , 2012, Journal of the American Chemical Society.

[2]  B. Cravatt,et al.  Activity-based probes for proteomic profiling of histone deacetylase complexes , 2007, Proceedings of the National Academy of Sciences.

[3]  Bifeng Liu,et al.  Single-cell chemical proteomics with an activity-based probe: identification of low-copy membrane proteins on primary neurons. , 2014, Angewandte Chemie.

[4]  Yuan Luo,et al.  Development and use of clickable activity based protein profiling agents for protein arginine deiminase 4. , 2011, ACS chemical biology.

[5]  J. Taunton,et al.  Selective targeting of distinct active site nucleophiles by irreversible SRC-family kinase inhibitors. , 2012, Journal of the American Chemical Society.

[6]  Raymond C Stevens,et al.  Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. , 2009, Chemistry & biology.

[7]  J. Chang,et al.  Proteome-wide reactivity profiling identifies diverse carbamate chemotypes tuned for serine hydrolase inhibition. , 2013, ACS chemical biology.

[8]  B. Cravatt,et al.  Chemical proteomic probes for profiling cytochrome p450 activities and drug interactions in vivo. , 2007, Chemistry & biology.

[9]  Steven J Brown,et al.  Confirming target engagement for reversible inhibitors in vivo by kinetically tuned activity-based probes. , 2012, Journal of the American Chemical Society.

[10]  Benedikt M Kessler,et al.  Chemistry in living cells: detection of active proteasomes by a two-step labeling strategy. , 2003, Angewandte Chemie.

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

[12]  B. Cravatt,et al.  Proteome-wide Mapping of Cholesterol-Interacting Proteins in Mammalian Cells , 2013, Nature Methods.

[13]  N. Gray,et al.  In situ kinase profiling reveals functionally relevant properties of native kinases. , 2011, Chemistry & biology.

[14]  R. Fischer,et al.  Endocytosis targets exogenous material selectively to cathepsin S in live human dendritic cells, while cell‐penetrating peptides mediate nonselective transport to cysteine cathepsins , 2007, Journal of leukocyte biology.

[15]  D. Figeys,et al.  A New Chemical Probe for Phosphatidylinositol Kinase Activity , 2014, Chembiochem : a European journal of chemical biology.

[16]  H. Overkleeft,et al.  Bioorthogonal chemistry: applications in activity-based protein profiling. , 2011, Accounts of chemical research.

[17]  A. Narayanan,et al.  Sulfonyl fluorides as privileged warheads in chemical biology , 2015, Chemical science.

[18]  Karunakaran A Kalesh,et al.  Target profiling of zerumbone using a novel cell-permeable clickable probe and quantitative chemical proteomics. , 2015, Chemical communications.

[19]  Bernhard Kuster,et al.  Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors , 2007, Nature Biotechnology.

[20]  M. Bogyo,et al.  Activity-based profiling of proteases. , 2014, Annual review of biochemistry.

[21]  Douglas H. Thamm,et al.  The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy , 2010, Proceedings of the National Academy of Sciences.

[22]  M. Bogyo,et al.  A nonpeptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages. , 2012, Chemistry & biology.

[23]  C. Zhan,et al.  A bright approach to the immunoproteasome: development of LMP2/β1i-specific imaging probes. , 2012, Bioorganic & medicinal chemistry.

[24]  Alexander V. Statsyuk,et al.  Development of activity-based probes for ubiquitin and ubiquitin-like protein signaling pathways. , 2013, Journal of the American Chemical Society.

[25]  Shao Q Yao,et al.  Proteome profiling reveals potential cellular targets of staurosporine using a clickable cell-permeable probe. , 2011, Chemical communications.

[26]  G. A. van der Marel,et al.  Ultrasensitive in situ visualization of active glucocerebrosidase molecules. , 2010, Nature chemical biology.

[27]  Benjamin F. Cravatt,et al.  A roadmap to evaluate the proteome-wide selectivity of covalent kinase inhibitors , 2014, Nature chemical biology.

[28]  T. Wandless,et al.  A Cell-permeable, Activity-based Probe for Protein and Lipid Kinases* , 2005, Journal of Biological Chemistry.

[29]  Raymond E Moellering,et al.  How chemoproteomics can enable drug discovery and development. , 2012, Chemistry & biology.

[30]  E. Weerapana,et al.  Covalent protein modification: the current landscape of residue-specific electrophiles. , 2015, Current opinion in chemical biology.

[31]  A. Hermetter,et al.  Activity-Based Probes for Studying the Activity of Flavin-Dependent Oxidases and for the Protein Target Profiling of Monoamine Oxidase Inhibitors , 2012, Angewandte Chemie.

[32]  Jack Taunton,et al.  A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. , 2007, Nature chemical biology.

[33]  Ludovic C. Gillet,et al.  In-cell Selectivity Profiling of Serine Protease Inhibitors by Activity-based Proteomics*S , 2008, Molecular & Cellular Proteomics.

[34]  Shao Q Yao,et al.  Cell-based proteome profiling of potential dasatinib targets by use of affinity-based probes. , 2012, Journal of the American Chemical Society.

[35]  B. Cravatt,et al.  Mapping the Protein Interaction Landscape for Fully Functionalized Small-Molecule Probes in Human Cells , 2014, Journal of the American Chemical Society.

[36]  Younan Xia,et al.  Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry. , 2014, Angewandte Chemie.

[37]  S. Sieber,et al.  Showdomycin as a versatile chemical tool for the detection of pathogenesis-associated enzymes in bacteria. , 2010, Journal of the American Chemical Society.

[38]  Kate S Carroll,et al.  Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. , 2011, Nature chemical biology.

[39]  Nathanael S Gray,et al.  Developing irreversible inhibitors of the protein kinase cysteinome. , 2013, Chemistry & biology.

[40]  A. Burlingame,et al.  Hypothemicin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei , 2013, eLife.

[41]  Luke G Green,et al.  A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. , 2002, Angewandte Chemie.

[42]  S. Licht,et al.  An activity-based protein profiling probe for the nicotinic acetylcholine receptor. , 2008, Journal of the American Chemical Society.

[43]  B. Cravatt,et al.  Activity-based protein profiling for the functional annotation of enzymes , 2007, Nature Methods.

[44]  Brahma Ghosh,et al.  Target validation using in-cell small molecule clickable imaging probes , 2014 .

[45]  Daniel C. Liebler,et al.  Site-specific mapping and quantification of protein S-sulfenylation in cells , 2014, Nature Communications.

[46]  M. Wenk,et al.  Activity-based proteome profiling of potential cellular targets of Orlistat--an FDA-approved drug with anti-tumor activities. , 2010, Journal of the American Chemical Society.

[47]  E. Weerapana,et al.  Applications of Copper-Catalyzed Click Chemistry in Activity-Based Protein Profiling , 2014, Molecules.

[48]  A. Narayanan,et al.  Rational targeting of active-site tyrosine residues using sulfonyl fluoride probes. , 2015, ACS chemical biology.

[49]  M. Finn,et al.  Click chemistry in complex mixtures: bioorthogonal bioconjugation. , 2014, Chemistry & biology.

[50]  Peter G. Dodd,et al.  In-cell click labelling of small molecules to determine subcellular localisation , 2011, Journal of chemical biology.

[51]  Morten Meldal,et al.  Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. , 2002, The Journal of organic chemistry.