Expanding the Number of 'Druggable' Targets: Non-Enzymes and Protein-Protein Interactions

Chemical Biology and Drug Design

Volumn 81, Issue 1, 2013, Pages 22-32

  Makley, Leah N ^a   Gestwicki, Jason E ^a  

^a UNIVERSITY OF MICHIGAN   (United States)

Author keywords

Biological screening; Chemical biology; Drug discovery; Protein protein interaction; Virtual screening

Indexed keywords

ARTICLE; DEUTERIUM HYDROGEN EXCHANGE; HIGH THROUGHPUT SCREENING; HUMAN; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PATHOLOGY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN STRUCTURE; PROTEIN SYNTHESIS;

DRUG DESIGN; GENOME, HUMAN; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LIGANDS; PROTEIN INTERACTION MAPS; PROTEIN STABILITY; PROTEINS; SMALL MOLECULE LIBRARIES;

EID: 84871365798     PISSN: 17470277     EISSN: 17470285     Source Type: Journal    
DOI: 10.1111/cbdd.12066     Document Type: Article

References (118)

1. Overington J.P., Al-Lazikani B., Hopkins A.L. (2006) Opinion - how many drug targets are there? Nat Rev Drug Discovery;5:993-996.
2. Imming P., Sinning C., Meyer A. (2006) Opinion - drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discovery;5:821-834.
3. Rual J.F. et al. (2005) Towards a proteome-scale map of the human protein-protein interaction network. Nature;437:1173-1178.
4. Arkin M.R., Whitty A. (2009) The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions. Curr Opin Chem Biol;13:284-290.
5. Smith M.C., Gestwicki J.E. (2012) Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med;14:e16.
6. Thompson A.D. et al. (2012) Fine-tuning multiprotein complexes using small molecules. ACS Chem Biol;7:1311-1320.
7. Wendt M.D. et al. (2007) Discovery of a novel small molecule binding site of human survivin. Bioorg Med Chem Lett;17:3122-3129.
8. Renaud J.P., Delsuc M.A. (2009) Biophysical techniques for ligand screening and drug design. Curr Opin Pharmacol;9:622-628.
9. Holdgate G.A. et al. (2010) Affinity-based, biophysical methods to detect and analyze ligand binding to recombinant proteins: matching high information content with high throughput. J Struct Biol;172:142-157.
10. Dalvit C. et al. (2001) WaterLOGSY as a method for primary NMR screening: practical aspects and range of applicability. J Biomol NMR;21:349-359.
11. Mayer M., Meyer B. (1999) Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angew Chem Int Ed;38:1784-1788.
12. Hajduk P.J., Olejniczak E.T., Fesik S.W. (1997) One-dimensional relaxation- and diffusion-edited NMR methods for screening compounds that bind to macromolecules. J Am Chem Soc;119:12257-12261.
13. Scott D.E. et al. (2012) Fragment-based approaches in drug discovery and chemical biology. Biochemistry;51(25):4990-5003.
14. Brough P.A. et al. (2009) Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2, 3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem;52:4794-4809.
15. Stockman B.J. et al. (2009) Identification of allosteric PIF-pocket ligands for PDK1 using NMR-based fragment screening and 1H-15N TROSY experiments. Chem Biol Drug Des;73:179-188.
16. Jahnke W. et al. (2005) Strategies for the NMR-based identification and optimization of allosteric protein kinase inhibitors. ChemBioChem;6:1607-1610.
17. Kristiansen M. et al. (2004) Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site. J Med Chem;47:3537-3545.
18. Krimm I., Lancelin J.M., Praly J.P. (2012) Binding evaluation of fragment-based scaffolds for probing allosteric enzymes. J Med Chem;55:1287-1295.
19. Jahnke W. et al. (2010) Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. Nat Chem Biol;6:660-666.
20. Hajduk P.J., Huth J.R., Fesik S.W. (2005) Druggability indices for protein targets derived from NMR-based screening data. J Med Chem;48:2518-2525.
21. Arkin M.R., Wells J.A. (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov;3:301-317.
22. Pagliaro L. et al. (2004) Emerging classes of protein-protein interaction inhibitors and new tools for their development. Curr Opin Chem Biol;8:442-449.
23. Altieri D.C. (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer;8:61-70.
24. Altieri D.C. (2012) Targeting survivin in cancer. Cancer. doi: 10.1016/j.canlet.2012.03.005.
25. Zaffaroni N., Pennati M., Daidone M.G. (2005) Survivin as a target for new anticancer interventions. J Cell Mol Med;9:360-372.
26. Carrasco R.A. et al. (2011) Antisense inhibition of survivin expression as a cancer therapeutic. Mol Cancer Ther;10:221-232.
27. Jonker N. et al. (2011) Recent developments in protein-ligand affinity mass spectrometry. Anal Bioanal Chem;399:2669-2681.
28. Wrenn S.J. et al. (2007) Synthetic ligands discovered by in vitro selection. J Am Chem Soc;129:13137-13143.
29. Clark M.A. (2010) Selecting chemicals: the emerging utility of DNA-encoded libraries. Curr Opin Chem Biol;14:396-403.
30. Vassilev L.T. et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science;303:844-848.
31. Koehler A.N., Shamji A.F., Schreiber S.L. (2003) Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. J Am Chem Soc;125:8420-8421.
32. Stanton B.Z. et al. (2009) A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol;5:154-156.
33. Peng L.F. et al. (2009) Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog. Bioorg Med Chem Lett;19:6319-6325.
34. Landry J.P., Fei Y., Zhu X.D. (2011) High throughput, label-free screening small molecule compound libraries for protein-ligands using combination of small molecule microarrays and a special ellipsometry-based optical scanner. Int Drug Discov; 8-13.
35. Landry J.P., Fei Y., Zhu X. (2012) Simultaneous measurement of 10, 000 protein-ligand affinity constants using microarray-based kinetic constant assays. Assay Drug Dev Technol;10:250-259.
36. Fei Y.Y. et al. (2008) A novel high-throughput scanning microscope for label-free detection of protein and small-molecule chemical microarrays. Rev Sci Instrum;79:013708.
37. Ulloa-Aguirre A. et al. (2004) Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic;5:821-837.
38. Kozarich J.W. (2009) The biochemistry of disease: desperately seeking syzygy. Annu Rev Biochem;78:55-63.
39. Pey A.L. et al. (2008) Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. J Clin Invest;118:2858-2867.
40. Sawkar A.R., D'Haeze W., Kelly J.W. (2006) Therapeutic strategies to ameliorate lysosomal storage disorders - a focus on Gaucher disease. Cell Mol Life Sci;63:1179-1192.
41. Yu Z., Sawkar A.R., Kelly J.W. (2007) Pharmacologic chaperoning as a strategy to treat Gaucher disease. FEBS J;274:4944-4950.
42. Tropak M.B. et al. (2007) High-throughput screening for human lysosomal beta-N-Acetyl hexosaminidase inhibitors acting as pharmacological chaperones. Chem Biol;14:153-164.
43. Wang Y. et al. (2007) Additive effect of multiple pharmacological chaperones on maturation of CFTR processing mutants. Biochem J;406:257-263.
44. Wang Y. et al. (2007) Modulating the folding of P-glycoprotein and cystic fibrosis transmembrane conductance regulator truncation mutants with pharmacological chaperones. Mol Pharmacol;71:751-758.
45. Hammarstrom P. et al. (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science;299:713-716.
46. Johnson S.M. et al. (2005) Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Acc Chem Res;38:911-921.
47. Johnson S.M. et al. (2012) The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol;421:185-203.
48. Stanger K. et al. (2012) Allosteric peptides bind a caspase zymogen and mediate caspase tetramerization. Nat Chem Biol;8:655-660.
49. Kuryatov A. et al. (2005) Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol;68:1839-1851.
50. Lester H.A. et al. (2009) Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. AAPS J;11:167-177.
51. Holdgate G.A., Ward W.H. (2005) Measurements of binding thermodynamics in drug discovery. Drug Discov Today;10:1543-1550.
52. Cummings M.D., Farnum M.A., Nelen M.I. (2006) Universal screening methods and applications of ThermoFluor. J Biomol Screen;11:854-863.
53. Niesen F.H., Berglund H., Vedadi M. (2007) The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat Protoc;2:2212-2221.
54. Lo M.C. et al. (2004) Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Anal Biochem;332:153-159.
55. DeSantis K. et al. (2012) Use of differential scanning fluorimetry as a high-throughput assay to identify nuclear receptor ligands. Nucl Recept Signal;10:e002.
56. Koblish H.K. et al. (2006) Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther;5:160-169.
57. Grasberger B.L. et al. (2005) Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem;48:909-912.
58. Parks D.J. et al. (2005) 1, 4-Benzodiazepine-2, 5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. Bioorg Med Chem Lett;15:765-770.
59. Sampson H.M. et al. (2011) Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR. Chem Biol;18:231-242.
60. Forneris F. et al. (2009) ThermoFAD, a Thermofluor-adapted flavin ad hoc detection system for protein folding and ligand binding. FEBS J;276:2833-2840.
61. Isom D.G. et al. (2010) A miniaturized technique for assessing protein thermodynamics and function using fast determination of quantitative cysteine reactivity. Proteins;79:1034-1047.
62. Ghaemmaghami S., Fitzgerald M.C., Oas T.G. (2000) A quantitative, high-throughput screen for protein stability. Proc Natl Acad Sci USA;97:8296-8301.
63. Tang L. et al. (2007) H/D exchange- and mass spectrometry-based strategy for the thermodynamic analysis of protein-ligand binding. Anal Chem;79:5869-5877.
64. Powell K.D., Fitzgerald M.C. (2004) High-throughput screening assay for the tunable selection of protein ligands. J Comb Chem;6:262-269.
65. Hopper E.D. et al. (2008) Throughput and efficiency of a mass spectrometry-based screening assay for protein-ligand binding detection. J Am Soc Mass Spectrom;19:1303-1311.
66. Dearmond P.D. et al. (2010) Discovery of novel cyclophilin A ligands using an H/D exchange- and mass spectrometry-based strategy. J Biomol Screen;15:1051-1062.
67. Perot S. et al. (2010) Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. Drug Discov Today;15:656-667.
68. Henrich S. et al. (2010) Computational approaches to identifying and characterizing protein binding sites for ligand design. J Mol Recognit;23:209-219.
69. An J.H., Totrov M., Abagyan R. (2005) Pocketome via comprehensive identification and classification of ligand binding envelopes. Mol Cell Proteomics;4:752-761.
70. Kozakov D. et al. (2011) Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci USA;108:13528-13533.
71. Mattos C., Ringe D. (1996) Locating and characterizing binding sites on proteins. Nat Biotechnol;14:595-599.
72. Lexa K.W., Carlson H.A. (2010) Full protein flexibility is essential for proper hot-spot mapping. J Am Chem Soc;133:200-202.
73. Cheng A.C. et al. (2007) Structure-based maximal affinity model predicts small-molecule druggability. Nat Biotechnol;25:71-75.
74. Halgren T.A. (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model;49:377-389.
75. Zhong S., MacKerell A.D. Jr (2007) Binding response: a descriptor for selecting ligand binding site on protein surfaces. J Chem Inf Model;47:2303-2315.
76. Nayal M., Honig B. (2006) On the nature of cavities on protein surfaces: application to the identification of drug-binding sites. Proteins;63:892-906.
77. Dar A.C., Shokat K.M. (2011) The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem;80:769-795.
78. Chang L. et al. (2011) Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism. Chem Biol;18:210-221.
79. Bauer R.A., Wurst J.M., Tan D.S. (2010) Expanding the range of 'druggable' targets with natural product-based libraries: an academic perspective. Curr Opin Chem Biol;14:308-314.
80. Dandapani S., Marcaurelle L.A. (2010) Grand challenge commentary: accessing new chemical space for 'undruggable' targets. Nat Chem Biol;6:861-863.
81. Sperandio O. et al. (2010) Rationalizing the chemical space of protein-protein interaction inhibitors. Drug Discov Today;15:220-229.
82. Smith M.C., Gestwicki J.E. (2012) Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med;14:e16.
83. Schreiber S.L. (2009) Organic chemistry: molecular diversity by design. Nature;457:153-154.
84. Galloway W.R., Isidro-Llobet A., Spring D.R. (2010) Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun;1:80.
85. Burke M.D., Schreiber S.L. (2004) A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed Engl;43:46-58.
86. Isidro-Llobet A. et al. (2011) Diversity-oriented synthesis of macrocyclic peptidomimetics. Proc Natl Acad Sci USA;108:6793-6798.
87. Renner S. et al. (2011) Recent trends and observations in the design of high-quality screening collections. Future Med Chem;3:751-766.
88. Boldi A.M. (2004) Libraries from natural product-like scaffolds. Curr Opin Chem Biol;8:281-286.
89. Clardy J., Walsh C. (2004) Lessons from natural molecules. Nature;432:829-837.
90. Harvey A.L. (2007) Natural products as a screening resource. Curr Opin Chem Biol;11:480-484.
91. Harvey A.L. (2008) Natural products in drug discovery. Drug Discov Today;13:894-901.
92. Bottcher T., Pitscheider M., Sieber S.A. (2010) Natural products and their biological targets: proteomic and metabolomic labeling strategies. Angew Chem Int Ed Engl;49:2680-2698.
93. Hopkins A.L., Groom C.R. (2002) The druggable genome. Nat Rev Drug Discov;1:727-730.
94. Zhang L. et al. (2007) High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. Proc Natl Acad Sci USA;104:4606-4611.
95. Hegde N.S. et al. (2011) The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nat Chem;3:725-731.
96. Evans C.G., Chang L., Gestwicki J.E. (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem;53:4585-4602.
97. Koehn F.E., Carter G.T. (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov;4:206-220.
98. Lam K.S., Lebl M., Krchnak V. (1997) The "one-bead-one-compound" combinatorial library method. Chem Rev;97:411-448.
99. Chen X. et al. (2011) Expanded polyglutamine-binding peptoid as a novel therapeutic agent for treatment of Huntington's disease. Chem Biol;18:1113-1125.
100. Zuckermann R.N., Kodadek T. (2009) Peptoids as potential therapeutics. Curr Opin Mol Ther;11:299-307.
101. Pande J., Szewczyk M.M., Grover A.K. (2010) Phage display: concept, innovations, applications and future. Biotechnol Adv;28:849-858.
102. Audie J., Boyd C. (2010) The synergistic use of computation, chemistry and biology to discover novel peptide-based drugs: the time is right. Curr Pharm Des;16:567-582.
103. Harrison R.S. et al. (2010) Downsizing human, bacterial, and viral proteins to short water-stable alpha helices that maintain biological potency. Proc Natl Acad Sci USA;107:11686-11691.
104. Verdine G.L., Hilinski G.J. (2012) All-hydrocarbon stapled peptides as Synthetic Cell-Accessible Mini-Proteins. Drug Discov Today;9:e41-e47.
105. Kawamoto S.A. et al. (2012) Design of triazole-stapled BCL9 alpha-helical peptides to target the beta-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction. J Med Chem;55:1137-1146.
106. Madden M.M. et al. (2011) Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition. Bioorg Med Chem Lett;21:1472-1475.
107. Moellering R.E. et al. (2009) Direct inhibition of the NOTCH transcription factor complex. Nature;462:182-188.
108. Liu T. et al. (2009) Synthesis and screening of a cyclic peptide library: discovery of small-molecule ligands against human prolactin receptor. Bioorg Med Chem;17:1026-1033.
109. Liu T. et al. (2011) High-throughput screening of one-bead-one-compound libraries: identification of cyclic peptidyl inhibitors against calcineurin/NFAT interaction. ACS Comb Sci;13:537-546.
110. Kleiner R.E., Dumelin C.E., Liu D.R. (2011) Small-molecule discovery from DNA-encoded chemical libraries. Chem Soc Rev;40:5707-5717.
111. Mannocci L. et al. (2011) 20years of DNA-encoded chemical libraries. Chem Commun (Camb);47:12747-12753.
112. Gartner Z.J., Kanan M.W., Liu D.R. (2002) Expanding the reaction scope of DNA-templated synthesis. Angew Chem Int Ed Engl;41:1796-1800.
113. Leach A.R., Hann M.M. (2011) Molecular complexity and fragment-based drug discovery: ten years on. Curr Opin Chem Biol;15:489-496.
114. Edfeldt F.N., Folmer R.H., Breeze A.L. (2011) Fragment screening to predict druggability (ligandability) and lead discovery success. Drug Discov Today;16:284-287.
115. Murray C.W., Rees D.C. (2009) The rise of fragment-based drug discovery. Nat Chem;1:187-192.
116. Carr R.A. et al. (2005) Fragment-based lead discovery: leads by design. Drug Discov Today;10:987-992.
117. Keseru G.M., Makara G.M. (2009) The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov;8:203-212.
118. Drewry D.H., Macarron R. (2010) Enhancements of screening collections to address areas of unmet medical need: an industry perspective. Curr Opin Chem Biol;14:289-298.