Phenotypic screening and fragment-based approaches to the discovery of small-molecule bromodomain ligands

Future Medicinal Chemistry

Volumn 6, Issue 2, 2014, Pages 179-204

  Jennings, Laura E ^a   Measures, Angelina R ^a   Wilson, Brian G ^a   Conway, Stuart J ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 THIAZOLIDINONE; 3,5 DIMETHYLISOXAZOLE; BINDING PROTEIN; CPI 0610; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; I BET 762; ISOXAZOLE DERIVATIVE; LIGAND; LYSINE; OTX 015; RVX 208; SMALL MOLECULE BROMODOMAIN LIGAND; UNCLASSIFIED DRUG;

CARBOXY TERMINAL SEQUENCE; DRUG DEVELOPMENT; DRUG SCREENING; FRAGMENT BASED DRUG DISCOVERY; HUMAN; LIGAND BINDING; LUCIFERASE ASSAY; MOLECULAR PROBE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; TRANSCRIPTION REGULATION;

APOLIPOPROTEIN A-I; BINDING SITES; DRUG DESIGN; HUMANS; LIGANDS; MOLECULAR DYNAMICS SIMULATION; PROTEIN STRUCTURE, TERTIARY; PROTEIN-SERINE-THREONINE KINASES; SMALL MOLECULE LIBRARIES;

EID: 84893200428     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.13.197     Document Type: Review

References (90)

1. Zeng L, Li J, Muller M et al. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J. Am. Chem. Soc. 127(8), 2376-2377 (2005
2. Sachchidanand, Resnick-Silverman L, Yan S et al. Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. Chem. Biol. 13(1), 81-90 (2006
3. Nicodeme E, Jeffrey KL, Schaefer U et al. Suppression of inflammation by a synthetic histone mimic. Nature 468(7327), 1119-1123 (2010
4. Chung C-W, Coste H, White JH et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem. 54(11), 3827-3838 (2011
5. Bailey D, Jahagirdar R, Gordon A et al. RVX-208: A small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J. Am. Coll. Cardiol. 55(23), 2580-2589 (2010
6. Khmelnitsky YL, Mozhaev VV, Cotterill IC et al. In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2- hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208). Eur. J. Med. Chem. 64C, 121-128 (2013
7. Filippakopoulos P, Qi J, Picaud S et al. Selective inhibition of BET bromodomains. Nature 468(7327), 1067-1073 (2010
8. Bonetti P, Ponzoni M, Tibiletti MG et al. The BRD-inhibitor OTX015 shows pre-clinical activity in diffuse large B-cell lymphoma (DLBCL). Eur. J. Cancer. 48(Suppl. 6), 163-163 (2012
9. Bonetti P, Boi M, Ponzoni M et al. The BRD-inhibitor OTX015 is active in pre-clinical models of mature B-cell lymphoid tumors. Blood 120(21), abstract 1657 (2012
10. Boi M, Bonetti P, Ponzoni M et al. The BRD-inhibitor OTX015 shows pre-clinical activity in anaplastic large T-cell lymphoma (ALCL). Blood 120(21), abstract 4872 (2012
11. Dawson MA, Prinjha RK, Dittmann A et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia. Nature 478(7370), 529-533 (2011
12. Chung C-W, Dean AW, Woolven JM, Bamborough P. Fragment-based discovery of bromodomain inhibitors part 1: Inhibitor binding modes and implications for lead discovery. J. Med. Chem. 55(2), 576-586 (2012
13. Bamborough P, Diallo H, Goodacre JD et al. Fragment-based discovery of bromodomain inhibitors part 2: Optimization of phenylisoxazole sulfonamides. J. Med. Chem. 55(2), 587-596 (2012
14. Hewings DS, Wang M, Philpott M et al. 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J. Med. Chem. 54(19), 6761-6770 (2011
15. Hay D, Fedorov O, Filippakopoulos P et al. The design and synthesis of 5 and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains. Med. Chem. Commun. 4, 140-144 (2013
16. Hewings DS, Fedorov O, Filippakopoulos P et al. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J. Med. Chem. 56(8), 3217-3227 (2013
17. Fish PV, Filippakopoulos P, Bish G et al. Identification of a chemical probe for bromo and extra c-Terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem. 55(22), 9831-9837 (2012
18. Zhao L, Cao D, Chen T et al. Fragment-based drug discovery of 2-Thiazolidinones as inhibitors of the histone reader BRD4 bromodomain. J. Med. Chem. 56(10), 3833-3851 (2013
19. Chung C-W, Witherington J. Progress in the discovery of small-molecule inhibitors of bromodomain-histone interactions. J. Biomol. Screen. 16(10), 1170-1185 (2011
20. Chung C-W, Tough DF. Bromodomains: A new target class for small molecule drug discovery. Drug Discov. Today: Ther. Strateg. 9,(2-3), e111-e120 (2012
21. Prinjha RK, Witherington J, Lee K. Place your BETs: The therapeutic potential of bromodomains. Trends Pharmacol. Sci. 33(3), 146-153 (2012
22. Conway SJ. Bromodomains: Are readers right for epigenetic therapy? ACS Med. Chem. Lett. 3, 691-694 (2012
23. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: A new frontier for drug discovery. Nat. Rev. Drug Disc. 11(5), 384-400 (2012
24. Hewings DS, Rooney TPC, Jennings LE et al. Progress in the development and application of small molecule inhibitors of bromodomain-Acetyl-lysine interactions. J. Med. Chem. 55(22), 9393-9413 (2012
25. Furdas SD, Carlino L, Sippl W, Jung M. Inhibition of bromodomain-mediated protein-protein interactions as a novel therapeutic strategy. Med. Chem. Commun. 3(2), 123-134 (2012
26. Umehara T, Nakamura Y, Jang MK et al. Structural basis for acetylated histone H4 recognition by the human BRD2 bromodomain. J. Biol. Chem. 285(10), 7610-7618 (2010
27. Mirguet O, Lamotte Y, Donche F et al. From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151. Bioorg. Med. Chem. Lett. 22(8), 2963-2967 (2012
28. Seal J, Lamotte Y, Donche F et al. Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A). Bioorg. Med. Chem. Lett. 22(8), 2968-2972 (2012
29. Mirguet O, Lamotte Y, Chung C-W et al. Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem doi:10.1002/cmdc.201300259 (2013) (Epub ahead of print
30. Filippakopoulos P, Picaud S, Mangos M et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149(1), 214-231 (2012
31. Owen DR, Trzupek JD. Epigenetic drugs that do not target enzyme activity. Drug Discov. Today Technol. doi:10.1016-j.ddtec.10.008 (2012) (In press
32. Wu X, Schultz PG. Synthesis at the interface of chemistry and biology. J. Am. Chem. Soc. 131(35), 12497-12515 (2009
33. Filippakopoulos P, Picaud S, Fedorov O et al. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg. Med. Chem. 20(6), 1878-1886 (2012
34. Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399(6735), 491-496 (1999
35. Mujtaba S, He Y, Zeng L et al. Structural basis of lysine-Acetylated HIV-1 Tat recognition by PCAF bromodomain. Mol. Cell. 9(3), 575-586 (2002
36. Pan C, Mezei M, Mujtaba S et al. Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-Associated factor. J. Med. Chem. 50(10), 2285-2288 (2007
37. Wang Q, Wang R, Zhang B, Zhang S, Zheng Y, Wang Z. Small organic molecules targeting PCAF bromodomain as potent inhibitors of HIV-1 replication. Med. Chem. Commun. 4(4), 737-740 (2013
38. Bedford DC, Kasper LH, Fukuyama T, Brindle PK. Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics 5(1), 9-15 (2010
39. Mujtaba S, He Y, Zeng L et al. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol. Cell. 13(2), 251-263 (2004
40. Borah JC, Mujtaba S, Karakikes I et al. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem. Biol. 18(4), 531-541 (2011
41. Gehling VS, Hewitt MC, Vaswani RG et al. Discovery, design, and optimization of isoxazole azepine BET inhibitors. ACS Med. Chem. Lett. 4(9), 835-840 (2013
42. Philpott M, Yang J, Tumber T et al. Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery. Mol. BioSyst. 7(10), 2899-2908 (2011
43. Hopkins AL, Groom CR, Alex A. Ligand efficiency: A useful metric for lead selection. Drug Discov. Today. 9(10), 430-431 (2004
44. Picaud S, Da Costa D, Thanasopoulou A et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res. 73(11), 3336-3346 (2013
45. Vidler LR, Filippakopoulos P, Fedorov O et al. Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening. J. Med. Chem. 56(20), 8073-8088 (2013
46. Edfeldt FNB, Folmer RHA, Breeze AL. Fragment screening to predict druggability (ligandability) and lead discovery success. Drug Discov. Today 16(7-8), 284-287 (2011
47. Nicholls SJ, Gordon A, Johansson J et al. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-Treated patients with stable coronary artery disease a randomized controlled trial. J. Am. Coll. Cardiol. 57(9), 1111-1119 (2011
48. Nicholls SJ, Gordon A, Johannson J et al. ApoA-I induction as a potential cardioprotective strategy: Rationale for the SUSTAIN and ASSURE studies. Cardiovasc Drugs Ther. 26(2), 181-187 (2012
49. Tamkun JW, Deuring R, Scott MP et al. brahma: A regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68(3), 561-572 (1992
50. Haynes SR, Dollard C, Winston F, Beck S, Trowsdale J, Dawid IB. The bromodomain: A conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Res. 20(10), 2603 (1992
51. Winston F, Allis C. The bromodomain: A chromatin-Targeting module? Nat. Struct. Biol. 6(7), 601-604 (1999
52. Chung C-W. Small molecule bromodomain inhibitors: Extending the druggable genome. Prog. Med. Chem. 51, 1-55 (2012
53. Zuber J, Shi J, Wang E et al. RNAi screen identifies BRD4 as a therapeutic target in acute myeloid leukemia. Nature 478(7370), 524-528 (2011
54. Mertz JA, Conery AR, Bryant BM et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108(40), 16669-16674 (2011
55. Wilson AJ. Inhibition of protein-protein interactions using designed molecules. Chem. Soc. Rev. 38(12), 3289-3300 (2009
56. Vidler LR, Brown N, Knapp S, Hoelder S. Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites. J. Med. Chem. 55(17), 7346-7359 (2012
57. Zhang G, Sanchez R, Zhou M-M. Scaling the druggability landscape of human bromodomains, a new class of drug targets. J. Med. Chem. 55(17), 7342-7345 (2012
58. Brennan P, Filippakopoulos P, Knapp S. The therapeutic potential of acetyl-lysine and methyl-lysine effector domains. Drug Discov. Today: Ther. Strategies 9(2-3), e101-e110 (2012
59. Mirguet O, Gosmini R, Toum J et al. Discovery of epigenetic regulator I-BET762: Lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J. Med. Chem. 56(19), 7501-7515 (2013
60. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Disc. 6(11), 881-890 (2007
61. Matzuk MM, McKeown MR, Filippakopoulos P et al. Small-molecule inhibition of BRDT for male contraception. Cell 150(4), 673-684 (2012
62. Puissant A, Frumm SM, Alexe G et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3(3), 308-323 (2013
63. Fierz B, Kilic S, Hieb AR, Luger K, Muir TW. Stability of nucleosomes containing homogenously ubiquitylated H2A and H2B prepared using semisynthesis. J. Am. Chem. Soc. 134(48), 19548-19551 (2012
64. Lange UC, Schneider R. What an epigenome remembers. Bioessays 32(8), 659-668 (2010
65. Bunnage ME. Getting pharmaceutical R&D back on target. Nat. Chem. Biol. 7(6), 335-339 (2011
66. Zeng L, Zhou M. Bromodomain: An acetyl-lysine binding domain. FEBS Lett. 513(1), 124-128 (2002
67. Filippakopoulos P, Knapp S. The bromodomain interaction module. FEBS Lett. 586(17), 2692-2704 (2012
68. Kornberg RD, Thomas JO. Chromatin structure; oligomers of the histones. Science 184(4139), 865-868 (1974
69. Kornberg RD. Chromatin structure: A repeating unit of histones and DNA. Science 184(4139), 868-871 (1974
70. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389(6648), 251-260 (1997
71. Allfrey V, Faulkner R, Mirsky A. Acetylation and Methylation of Histones and their Possible Role in Regulation of RNA Synthesis. Proc. Natl Acad. Sci. USA 51(5), 786-794 (1964
72. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 403(6765), 41-45 (2000
73. Turner BM. Histone acetylation and an epigenetic code. Bioessays 22(9), 836-845 (2000
74. Schreiber SL, Bernstein BE. Signaling network model of chromatin. Cell 111(6), 771-778 (2002
75. Gardner KE, Allis CD, Strahl BD. Operating on chromatin, a colorful language where context matters. J. Mol. Biol. 409(1), 36-46 (2011
76. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 389(6649), 349-352 (1997
77. Jenuwein T, Allis CD. Translating the histone code. Science 293(5532), 1074-1080 (2001
78. Bernstein BE, Schreiber SL. Global approaches to chromatin. Chem. Biol. 9(11), 1167-1173 (2002
79. Turner BM. The adjustable nucleosome: An epigenetic signaling module. Trends Genet. 28(9), 436-444 (2012
80. Bird A. Perceptions of epigenetics. Nature 447(7143), 396-398 (2007
81. Ptashne M. Epigenetics: Core misconcept. Proc. Natl Acad. Sci. USA 110(18), 7101-7103 (2013
82. Bakker A, Caricasole A, Gaviraghi G et al. How to achieve confidence in drug discovery and development: Managing risk (from a reductionist to a holistic approach). ChemMedChem 4(6), 923-933 (2009
83. Lipinski CA. Phenotypic and In Vivo Screening: Lead Discovery and Drug Repurposing. Royal Society of Chemistry, London, UK, 86 (2012
84. Arrowsmith J, Miller P. Trial Watch: Phase II and Phase III attrition rates 2011-2012. Nat. Rev. Drug Disc. 12(8), 569 (2013
85. Murray CW, Verdonk ML, Rees DC. Experiences in fragment-based drug discovery. Trends Pharmacol. Sci. 33(5), 224-232 (2012
86. Congreve M, Chessari G, Tisi D, Woodhead AJ. Recent developments in fragment-based drug discovery. J. Med. Chem. 51(13), 3661-3680 (2008
87. Congreve M, Carr R, Murray C, Jhoti H. A rule of threé for fragment-based lead discovery? Drug Discov. Today 8(19), 876-877 (2003
88. Scott DE, Coyne AG, Hudson SA, Abell C. Fragment-based approaches in drug discovery and chemical biology. Biochemistry 51(25), 4990-5003 (2012
89. Baker M. Fragment-based lead discovery grows up. Nat. Rev. Drug Disc. 12(1), 5-7 (2013
90. van Rooij E, Olson EN. MicroRNA therapeutics for cardiovascular disease: Opportunities and obstacles. Nat. Rev. Drug Disc. 11(11), 860-872 (2012