Targeting low-druggability bromodomains: Fragment based screening and inhibitor design against the BAZ2B bromodomain

Journal of Medicinal Chemistry

Volumn 56, Issue 24, 2013, Pages 10183-10187

  Ferguson, Fleur M ^a   Fedorov, Oleg ^b   Chaikuad, Apirat ^b   Philpott, Martin ^b   Muniz, Joao R C ^b,d   Felletar, Ildiko ^b,e   Von Delft, Frank ^b   Heightman, Tom ^b,f   Knapp, Stefan ^b   Abell, Chris ^a,c   Ciulli, Alessio ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c UNIVERSITY OF DUNDEE   (United Kingdom)

^d UNIVERSITY OF SÃO PAULO   (Brazil)

^e UNIVERSITY OF SUSSEX   (United Kingdom)

^f ASTEX PHARMACEUTICALS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BROMODOMAIN INHIBITOR; PROTEIN INHIBITOR; UNCLASSIFIED DRUG; ZINC FINGER PROTEIN; ZINC FINGER PROTEIN 2B;

ARTICLE; BINDING SITE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG TARGETING; HYDROGEN BOND; PHYLOGENETIC TREE; PROMOTER REGION; PROTEIN DOMAIN;

EID: 84891341157     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401582c     Document Type: Article

References (18)

1. Muller, S.; Filippakopoulos, P.; Knapp, S. Bromodomains as therapeutic targets Expert Rev. Mol. Med. 2011, 13, e29
2. Barbieri, I.; Cannizzaro, E.; Dawson, M. A. Bromodomains as therapeutic targets in cancer Brief Funct. Genomics 2013, 12 (3) 219-230
3. Vidler, L. R.; Brown, N.; Knapp, S.; Hoelder, S. Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites J. Med. Chem. 2012, 55 (17) 7346-7359
4. Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.; Fedorov, O.; Morse, E. M.; Keates, T.; Hickman, T. T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M. R.; Wang, Y.; Christie, A. L.; West, N.; Cameron, M. J.; Schwartz, B.; Heightman, T. D.; La Thangue, N.; French, C. A.; Wiest, O.; Kung, A. L.; Knapp, S.; Bradner, J. E. Selective inhibition of BET bromodomains Nature 2010, 468 (7327) 1067-1073
5. Nicodeme, E.; Jeffrey, K. L.; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C.-w.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; White, J.; Kirilovsky, J.; Rice, C. M.; Lora, J. M.; Prinjha, R. K.; Lee, K.; Tarakhovsky, A. Suppression of inflammation by a synthetic histone mimic Nature 2010, 468 (7327) 1119-1123
6. Fish, P. V.; Filippakopoulos, P.; Bish, G.; Brennan, P. E.; Bunnage, M. E.; Cook, A. S.; Federov, O.; Gerstenberger, B. S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D. R.; Philpott, M.; Picaud, S.; Primiano, M. J.; Ralph, M. J.; Sciammetta, N.; Trzupek, J. D. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit J. Med. Chem. 2012, 55 (22) 9831-9837
7. Philpott, M.; Yang, J.; Tumber, T.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Keates, T.; Felletar, I.; Ciulli, A.; Knapp, S.; Heightman, T. D. Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery Mol. BioSyst. 2011, 7 (10) 2899-2908
8. Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. A "rule of three" for fragment-based lead discovery? Drug Discovery Today 2003, 8 (19) 876-877
9. Mayer, M.; Meyer, B. Characterization of ligand binding by saturation transfer difference NMR spectroscopy Angew. Chem., Int. Ed. 1999, 38 (12) 1784-1788
10. Carr, H. Y.; Purcell, E. M. Effects of diffusion on free precession in nuclear magnetic resonance experiments Phys. Rev. 1954, 94 (3) 630-638
11. Dalvit, C.; Pevarello, P.; Tato', M.; Veronesi, M.; Vulpetti, A.; Sundstrom, M. Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water J. Biol. NMR 2000, 18 (1) 65-68
12. Filippakopoulos, P.; Picaud, S.; Mangos, M.; Keates, T.; Lambert, J.-P.; Barsyte-Lovejoy, D.; Felletar, I.; Volkmer, R.; Müller, S.; Pawson, T.; Gingras, A.-C.; Arrowsmith, C. H.; Knapp, S. Histone recognition and large-scale structural analysis of the human bromodomain family Cell 2012, 149 (1) 214-231
13. Magno, A.; Steiner, S.; Caflisch, A. Mechanism and kinetics of acetyl-lysine binding to bromodomains J. Chem. Theory Comput. 2013, 9 (9) 4225-4232
14. Wilcken, R.; Zimmermann, M. O.; Lange, A.; Joerger, A. C.; Boeckler, F. M. Principles and applications of halogen bonding in medicinal chemistry and chemical biology J. Med. Chem. 2012, 56 (4) 1363-1388
15. Glide, version 5.9; Schrödinger, LLC: New York, NY, 2013.
16. Brenke, R.; Kozakov, D.; Chuang, G.-Y.; Beglov, D.; Hall, D.; Landon, M. R.; Mattos, C.; Vajda, S. Fragment-based identification of druggable "hot spots" of proteins using Fourier domain correlation techniques Bioinformatics 2009, 25 (5) 621-627
17. Hewings, D. S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.; Heightman, T. D. 3,5-Dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands J. Med. Chem. 2011, 54 (19) 6761-6770
18. GSK2801: A Selective Chemical Probe for BAZ2B/A Bromodomains. http://www.thesgc.org/scientists/chemical-probes/GSK2801 (accessed August 5, 2013).