Protein-protein interaction modulator drug discovery: Past efforts and future opportunities using a rich source of low- and high-throughput screening assays

Expert Opinion on Drug Discovery

Volumn 9, Issue 12, 2014, Pages 1393-1404

  Gul, Sheraz ^a   Hadian, Kamyar ^b  

^a FRAUNHOFER INSTITUTE FOR MOLECULAR BIOLOGY AND APPLIED ECOLOGY IME   (Germany)

^b INSTITUTE OF EPIDEMIOLOGY   (Germany)

Author keywords

Assay formats; Drug discovery; High throughput screening; Protein protein interaction; Small molecule libraries

Indexed keywords

PROTEIN INHIBITOR; PROTEIN PROTEIN INTERACTION MODULATOR; UNCLASSIFIED DRUG; PROTEIN;

AMPLIFIED LUMINESCENT PROXIMITY HOMOGENEOUS ASSAY SCREEN; ARTICLE; BIMOLECULAR FLUORESCENCE COMPLEMENTATION ASSAY; BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; ENZYME LINKED IMMUNOSORBENT ASSAY; FLUORESCENCE POLARIZATION; FLUORESCENCE RESONANCE ENERGY TRANSFER; FLUORESCENCE TWO HYBRID ASSAY; FRAGMENT BASED DRUG DISCOVERY; HIGH THROUGHPUT SCREENING; IN SITU PROXIMITY LIGATION ASSAY; ISOTHERMAL TITRATION CALORIMETRY; LOW THROUGHPUT SCREENING ASSAY; MICROSCALE THERMOPHORESIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTEIN PROTEIN INTERACTION; PULL DOWN ASSAY; SURFACE PLASMON RESONANCE; TIME RESOLVED FORSTER RESONANCE ENERGY TRANSFER; X RAY CRYSTALLOGRAPHY; BIOASSAY; DRUG DEVELOPMENT; METABOLISM; PROTEIN ANALYSIS;

BIOLOGICAL ASSAY; DRUG DISCOVERY; HIGH-THROUGHPUT SCREENING ASSAYS; PROTEIN INTERACTION MAPPING; PROTEINS;

EID: 84912041026     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2014.954544     Document Type: Article

References (110)

1. Dixon SJ, Stockwell BR. Identifying druggable disease-modifying gene products. Curr Opin Chem Biol 2009;13(5-6):549-55
2. Blundell TL, Burke DF, Chirgadze D, et al. Protein-protein interactions in receptor activation and intracellular signalling. Biol Chem 2000;381(9-10):955-9
3. Jones S, Thornton JM. Principles of protein-protein interactions. Proc Natl Acad Sci USA 1996;93(1):13-20
4. Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there?. Nat Rev Drug Discov 2006;5(12):993-6
5. Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol 2012;6(2):155-76
6. Smith MC, Gestwicki JE. Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 2012;14:e16
7. Jubb H, Higueruelo P, Winter A, et al. Structural biology and drug discovery for protein-protein interactions. Trends Pharmacol Sci 2012;33(5):241-8
8. Wells JA, McClendon CL. Reaching for high-hanging fruit in Drug discovery at protein-protein interfaces. Nature 2007;450(7172):1001-9
9. Zinzalla G, Thurston DE. Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. Future Med Chem 2009;1(1):65-93
10. Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 2014;13(3):217-36
11. Kojima K, Burks JK, Arts J, et al. The novel tryptamine derivative JNJ-26854165 induces wild-Type p53- And E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. Mol Cancer Ther 2010;9(9):2545-57
12. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303(5659):844-8
13. Wasylyk C, Salvi R, Argentini M, et al. p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53. Oncogene 1999;18(11):1921-34
14. Bruncko M, Oost TK, Belli BA, et al. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 2007;50(4):641-62
15. Buchwald P. Small-molecule proteinprotein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life 2010;62(10):724-31
16. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435(7042):677-81
17. Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective smallmolecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 2005;49(11):4721-32
18. Peerlinck K, De Lepeleire I, Goldberg M, et al. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation 1993;88(4 Pt 1):1512-17
19. Colas P. High-Throughput screening assays to discover small-molecule inhibitors of protein interactions. Curr Drug Discov Technol 2008;5(3):190-9
20. Macarron R, Banks MN, Bojanic D, et al. Impact of high-Throughput screening in biomedical research. Nat Rev Drug Discov 2011;10(3):188-95
21. Swinney DC, Anthony J. How were new medicines discovered?. Nat Rev Drug Discov 2011;10(7):507-19
22. Swinney DC. Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin Pharmacol Ther 2013;93(4):299-301
23. Cai SX, Drewe J, Kasibhatla S. A chemical genetics approach for the discovery of apoptosis inducers: from phenotypic cell based HTS assay and structure-Activity relationship studies, to identification of potential anticancer agents and molecular targets. Curr Med Chem 2006;13(22):2627-44
24. Harner MJ, Frank AO, Fesik SW. Fragment-based drug discovery using NMR spectroscopy. J Biomol NMR 2013;56(2):65-75
25. Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in Drug discovery and development settings. Adv Drug Deliv Rev 2001;46(1-3):3-26
26. Chuprina A, Lukin O, Demoiseaux R, et al. Drug- And lead-likeness, target class, and molecular diversity analysis of 7.9 million commercially available organic compounds provided by 29 suppliers. J Chem Inf Model 2010;50(4):470-9
27. Schon A, Lam SY, Freire E. Thermodynamics-based drug design: strategies for inhibiting protein-protein interactions. Future Med Chem 2011;3(9):1129-37
28. Feng BY, Simeonov A, Jadhav A, et al. A high-Throughput screen for aggregation-based inhibition in a large compound library. J Med Chem 2007;50(10):2385-90
29. Leavitt S, Freire E. Direct measurement of protein binding energetics by isothermal titration calorimetry. Curr Opin Struct Biol 2001;11(5):560-6
30. Velazquez-Campoy A, Leavitt SA, Freire E. Characterization of proteinprotein interactions by isothermal titration calorimetry. Methods Mol Biol 2004;261:35-54
31. Trosset JY, Dalvit C, Knapp S, et al. Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 2006;64(1):60-7
32. Tanious FA, Nguyen B, Wilson WD. Biosensor-surface plasmon resonance methods for quantitative analysis of biomolecular interactions. Methods Cell Biol 2008;84:53-77
33. Torreri P, Ceccarini M, Macioce P, et al. Biomolecular interactions by Surface Plasmon Resonance technology. Ann Ist Super Sanita 2005;41(4):437-41
34. Fee CJ. Label-free, real-Time interaction and adsorption analysis 1: surface plasmon resonance. Methods Mol Biol 2013;996:287-312
35. Berggard T, Linse S, James P. Methods for the detection and analysis of proteinprotein interactions. Proteomics 2007;7(16):2833-42
36. Uvebrant K, da Graca Thrige D, Rosen A, et al. Discovery of selective small-molecule CD80 inhibitors. J Biomol Screen 2007;12(4):464-72
37. LaustedC HuZ. Hood, L. Label-free detection with surface plasmon resonance imaging. Methods Mol Biol 2011;723:321-33
38. Lausted C, Hu Z, Hood L, et al. SPR imaging for high throughput, label-free interaction analysis. Comb Chem High Throughput Screen 2009;12(8):741-51
39. Seidel SA, Dijkman PM, Lea WA, et al. Microscale thermophoresis quantifies biomolecular interactions under previously challenging conditions. Methods 2013;59(3):301-15
40. Wienken CJ, Baaske P, Rothbauer U, et al. Protein-binding assays in biological liquids using microscale thermophoresis. Nat Commun 2010;1:100
41. Seidel SA, Wienken CJ, Geissler S, et al. Label-free microscale thermophoresis discriminates sites and affinity of proteinligand binding. Angew Chem 2012;51(42):10656-9
42. Jerabek-Willemsen M, Wienken CJ, Braun D, et al. Molecular interaction studies using microscale thermophoresis. Assay Drug Dev Technol 2011;9(4):342-53
43. Shang X, Marchioni F, Sipes N, et al. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem Biol 2012;19(6):699-710
44. Bosco EE, Kumar S, Marchioni F, et al. Rational design of small molecule inhibitors targeting the Rac GTPase-p67 (phox) signaling axis in inflammation. Chem Biol 2012;19(2):228-42
45. Arkin MR, Glicksman MA, Fu H, et al. Inhibition of protein-protein interactions: non-cellular assay formats. In: Assay guidance manual. Eli Lilly and Company and the National Institutes of Health Chemical Genomics Center, Bethesda (MD); 2004
46. de la Roche M, Rutherford TJ, Gupta D, et al. An intrinsically labile alpha-helix abutting the BCL9-binding site of beta-catenin is required for its inhibition by carnosic acid. Nat Commun 2012;3:680
47. Keating SM, Clark KR, Stefanich LD, et al. Competition between intercellular adhesion molecule-1 and a smallmolecule antagonist for a common binding site on the alphal subunit of lymphocyte function-Associated antigen-1. Protein Sci 2006;15(2):290-303
48. Hadian K, Griesbach RA, Dornauer S, et al. NF-kappaB essential modulator (NEMO) interaction with linear and lys-63 ubiquitin chains contributes to NF-kappaB activation. J Biol Chem 2011;286(29):26107-17
49. Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 2004;6(1):33-43
50. Schechtman D, Mochly-Rosen D, Ron D. Glutathione S-Transferase pull-down assay. Methods Mol Biol 2003;233:345-50
51. Russell RB, Alber F, Aloy P, et al. A structural perspective on proteinprotein interactions. Curr Opin Struct Biol 2004;14(3):313-24
52. Xu Y, Matthews S. TROSY NMR spectroscopy of large soluble proteins. Top Curr Chem 2013;335:97-119
53. Duss O, Lukavsky PJ, Allain FH. Isotope labeling and segmental labeling of larger RNAs for NMR structural studies. Adv Exp Med Biol 2012;992:121-44
54. Hajduk PJ, Meadows RP, Fesik SW. NMR-based screening in Drug discovery. Q Rev Biophys 1999;32(3):211-40
55. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467(7315):596-9
56. Eglen RM, Reisine T, Roby P, et al. The use of AlphaScreen technology in HTS: current status. Curr Chem Genomics 2008;1:2-10
57. Glickman JF, Wu X, Mercuri R, et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen 2002;7(1):3-10
58. BaellJ B, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 2010;53(7):2719-40
59. Schorpp K, Rothenaigner I, Salmina E, et al. Identification of small-molecule frequent hitters from alphascreen highthroughput screens. J Biomol Screen 2013;19(5):715-26
60. Zimmermann G, Papke B, Ismail S, et al. Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature 2013;497(7451):638-42
61. Degorce F, Card A, Soh S, et al. HTRF: a technology tailored for drug discovery -A review of theoretical aspects and recent applications. Curr Chem Genomics 2009;3:22-32
62. Du Y, Fu RW, Lou B, et al. A timeresolved fluorescence resonance energy transfer assay for high-Throughput screening of 14-3-3 protein-protein interaction inhibitors. Assay Drug Dev Technol 2013;11(6):367-81
63. Jameson DM, Croney JC. Fluorescence polarization: past, present and future. Comb Chem High Throughput Screen 2003;6(3):167-73
64. Lea WA, Simeonov A. Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov 2011;6(1):17-32
65. Kenny CH, Ding W, Kelleher K, et al. Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. Anal Biochem 2003;323(2):224-33
66. Yoshimura C, Miyafusa T, Tsumoto K. Identification of small-molecule inhibitors of the human S100B-p53 interaction and evaluation of their activity in human melanoma cells. Bioorg Med Chem 2013;21(5):1109-15
67. Moerke NJ, Aktas H, Chen H, et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007;128(2):257-67
68. Truong K, Ikura M. The use of FRET imaging microscopy to detect proteinprotein interactions and protein conformational changes in vivo. Curr Opin Struct Biol 2001;11(5):573-8
69. Banning C, Votteler J, Hoffmann D, et al. A flow cytometry-based FRET assay to identify and analyse proteinprotein interactions in living cells. PLoS One 2010;5(2):e9344
70. Cryan LM, Habeshian KA, Caldwell TP, et al. Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay. J Biomol Screen 2013;18(6):714-25
71. Lam AJ, St-Pierre F, Gong Y, et al. Improving FRET dynamic range with bright green and red fluorescent proteins. Nat Methods 2012;9(10):1005-12
72. Bacart J, Corbel C, Jockers R, et al. The BRET technology and its application to screening assays. Biotechnol J 2008;3(3):311-24
73. Mazars A, Fahraeus R. Using BRET to study chemical compound-induced disruptions of the p53-HDM2 interactions in live cells. Biotechnol J 2010;5(4):377-84
74. Hu CD, Chinenov Y, Kerppola TK. Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell 2002;9(4):789-98
75. Kerppola TK. Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells. Ann Rev Biophy 2008;37:465-87
76. Kodama Y, Hu CD. Bimolecular fluorescence complementation (BiFC): a 5-year update and future perspectives. Biotechniques 2012;53(5):285-98
77. Wolff H, Hartl A, EilkenH M, et al. Live-cell assay for simultaneous monitoring of expression and interaction of proteins. Biotechniques 2006;41(6):688, 690, 692
78. Soderberg O, Gullberg M, Jarvius M, et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 2006;3(12):995-1000
79. Soderberg O, Leuchowius KJ, Gullberg M, et al. Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay. Methods 2008;45(3):227-32
80. Weibrecht I, Leuchowius KJ, Clausson CM, et al. Proximity ligation assays: a recent addition to the proteomics toolbox. Expert Rev Proteomics 2010;7(3):401-9
81. Zolghadr K, Mortusewicz O, Rothbauer U, et al. A fluorescent twohybrid assay for direct visualization of protein interactions in living cells. Mol Cell Proteomics 2008;7(11):2279-87
82. Yurlova L, Derks M, Buchfellner A, et al. The fluorescent two-hybrid assay to screen for protein-protein interaction inhibitors in live cells: targeting the interaction of p53 with Mdm2 and Mdm4. J Biomol Screen 2014;19(4):516-25
83. Kaboord B, Perr M. Isolation of proteins and protein complexes by immunoprecipitation. Methods Mol Biol 2008;424:349-64
84. Dr. PIAS - Druggable Protein-protein Interaction Assessment System. http:// www.drpias.net [Last accessed 4 August 2014]
85. Sugaya N, Furuya T. Dr. PIAS: an integrative system for assessing the druggability of protein-protein interactions. BMC Bioinformatics 2011;12:50
86. Sugaya N, Ikeda K. Assessing the druggability of protein-protein interactions by a supervised machinelearning method. BMC Bioinformatics 2009;10:263
87. Sugaya N, Kanai S, Furuya T. Dr. PIAS 2.0: an update of a database of predicted druggable protein-protein interactions. Database (Oxford) 2012;2012:bas034
88. Fletcher S, Prochownik EV. Small-molecule inhibitors of the Myc oncoprotein. Biochim Biophy Acta 2014. [Epub ahead of print]
89. Kiessling A, Sperl B, Hollis A, et al. Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. Chem Biol 2006;13(7):745-51
90. Patgiri A, Yadav KK, Arora PS, et al. An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol 2011;7(9):585-7
91. Davis RK, Chellappan S. Disrupting the Rb-Raf-1 interaction: a potential therapeutic target for cancer. Drug News Perspect 2008;21(6):331-5
92. Song H, Wang R, Wang S, et al. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc Natl Acad Sci USA 2005;102(13):4700-5
93. Gorczynski MJ, Grembecka J, Zhou Y, et al. Allosteric inhibition of the proteinprotein interaction between the leukemiaassociated proteins Runx1 and CBFbeta. Chem Biol 2007;14(10):1186-97
94. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature 2010;468(7327):1067-73
95. Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010;468(7327):1119-23
96. Bai L, Smith DC, Wang S. Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther 2014. [Epub ahead of print]
97. He MM, Smith AS, Oslob JD, et al. Small-molecule inhibition of TNF-Alpha. Science 2005;310(5750):1022-5
98. Raimundo BC, Oslob JD, Braisted AC, et al. Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: an approach for inhibiting protein-protein interactions. J Med Chem 2004;47(12):3111-30
99. Braisted AC, Oslob JD, Delano WL, et al. Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J Am Chem Soc 2003;125(13):3714-15
100. Margolles-Clark E, Kenyon NS, Ricordi C, et al. Effective and specific inhibition of the CD40-CD154 costimulatory interaction by a naphthalenesulphonic acid derivative. Chem Biol Drug Des 2010;76(4):305-13
101. Margolles-Clark E, Umland O, Kenyon NS, et al. Small-molecule costimulatory blockade: organic dye inhibitors of the CD40-CD154 interaction. J Mol Med 2009;87(11):1133-43
102. Gadek TR, Burdick DJ, McDowell RS, et al. Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 2002;295(5557):1086-9
103. Zhong M, Gadek TR, Bui M, et al. Discovery and development of potent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treating dry eye. ACS Med Chem Lett 2012;3(3):203-6
104. Christ F, Voet A, Marchand A, et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 2010;6(6):442-8
105. Merabet N, Dumond J, Collinet B, et al. New constrained "molecular tongs" designed to dissociate HIV-1 protease dimer. J Med Chem 2004;47(25):6392-400
106. Shultz MD, Ham YW, Lee SG, et al. Small-molecule dimerization inhibitors of wild-Type and mutant HIV protease: a focused library approach. J Am Chem Soc 2004;126(32):9886-7
107. Goudreau N, Cameron DR, Deziel R, et al. Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1-E2 proteinprotein interaction: a combined medicinal chemistry, NMR and computational chemistry approach. Bioorg Med Chem 2007;15(7):2690-700
108. White PW, Titolo S, Brault K, et al. Inhibition of human papillomavirus DNA replication by small molecule antagonists of the E1-E2 protein interaction. J Biol Chem 2003;278(29):26765-72
109. Lim PJ, Gallay PA. Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance. Curr Opin Virol 2014;8C:30-7
110. von Kleist L, Stahlschmidt W, Bulut H, et al. Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. Cell 2011;146(3):471-84