Design and characterization of bivalent BET inhibitors

Nature Chemical Biology

Volumn 12, Issue 12, 2016, Pages 1089-1096

  Tanaka, Minoru ^a,b   Roberts, Justin M ^a   Seo, Hyuk Soo ^a   Souza, Amanda ^a   Paulk, Joshiawa ^a   Scott, Thomas G ^a   Deangelo, Stephen L ^a   Dhe Paganon, Sirano ^a   Bradner, James E ^a,b,c  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 CHLOROPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETIC ACID TERT BUTYL ESTER; ANTINEOPLASTIC AGENT; BROMODOMAIN INHIBITOR; MT 1; UNCLASSIFIED DRUG; (+)-JQ1 COMPOUND; AZEPINE DERIVATIVE; BRD4 PROTEIN, HUMAN; LIGAND; MOLECULAR LIBRARY; NUCLEAR PROTEIN; TRANSCRIPTION FACTOR; TRIAZOLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BIOCHEMICAL ANALYSIS; CANCER INHIBITION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; FEMALE; HUMAN; HUMAN CELL; IC50; IN VIVO STUDY; LEUKEMIA; MOUSE; NONHUMAN; PLASMA HALF LIFE; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CELL PROLIFERATION; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG EFFECTS; METABOLISM; MOLECULAR LIBRARY; MOLECULAR MODEL; NEOPLASMS, EXPERIMENTAL; PATHOLOGY; PHARMACOLOGY; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; AZEPINES; CELL PROLIFERATION; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; HUMANS; LEUKEMIA; LIGANDS; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEOPLASMS, EXPERIMENTAL; NUCLEAR PROTEINS; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION FACTORS; TRIAZOLES;

EID: 84992313205     PISSN: 15524450     EISSN: 15524469     Source Type: Journal    
DOI: 10.1038/nchembio.2209     Document Type: Article

References (46)

1. Mammen, M., Choi, S.-K. & Whitesides, G. M. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Ed. Engl. 37, 2754-2794 (1998).
2. Monsigny, M., Mayer, R. & Roche, A. C. Sugar-lectin interactions: sugar clusters, lectin multivalency and avidity. Carbohydr. Lett. 4, 35-52 (2000).
3. Kiessling, L. L., Gestwicki, J. E. & Strong, L. E. Synthetic multivalent ligands in the exploration of cell-surface interactions. Curr. Opin. Chem. Biol. 4, 696-703 (2000).
4. Bach, A. et al. Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction. Angew. Chem. Int. Ed. Engl. 48, 9685-9689 (2009).
5. Illendula, A. et al. Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBF-SMMHC delays leukemia in mice. Science 347, 779-784 (2015).
6. Profit, A. A., Lee, T. R. & Lawrence, D. S. Bivalent inhibitors of protein tyrosine kinases. J. Am. Chem. Soc. 121, 280-283 (1999).
7. Sun, H. et al. Design, synthesis, and characterization of a potent, nonpeptide, cell-permeable, bivalent Smac mimetic that concurrently targets both the BIR2 and BIR3 domains in XIAP. J. Am. Chem. Soc. 129, 15279-15294 (2007).
8. Bach, A. et al. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl. Acad. Sci. USA 109, 3317-3322 (2012).
9. Filippakopoulos, P. & Knapp, S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 13, 337-356 (2014).
10. Zeng, L. & Zhou, M. M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124-128 (2002).
11. Smith, S. G. & Zhou, M. M. The bromodomain: a new target in emerging epigenetic medicine. ACS Chem. Biol. 11, 598-608 (2016).
12. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524-528 (2011).
13. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904-917 (2011).
14. Yang, Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535-545 (2005).
15. Krueger, B. J., Varzavand, K., Cooper, J. J. & Price, D. H. The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK. PLoS One 5, e12335 (2010).
16. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010).
17. Tanaka, M., Roberts, J. M., Qi, J. & Bradner, J. E. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010-2014). Pharm. Pat. Anal. 4, 261-284 (2015).
18. Schröder, S. et al. Two-pronged binding with bromodomain-containing protein 4 liberates positive transcription elongation factor b from inactive ribonucleoprotein complexes. J. Biol. Chem. 287, 1090-1099 (2012).
19. Baud, M. G. et al. Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science 346, 638-641 (2014).
20. Picaud, S. et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. USA 110, 19754-19759 (2013).
21. Zhang, G. et al. Down-regulation of NF-B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J. Biol. Chem. 287, 28840-28851 (2012).
22. McKeown, M. R. et al. Biased multicomponent reactions to develop novel bromodomain inhibitors. J. Med. Chem. 57, 9019-9027 (2014).
23. Roberts, J. M. & Bradner, J. E. A bead-based proximity assay for BRD4 ligand discovery. Curr. Protoc. Chem. Biol. 7, 263-278 (2015).
24. Dahlin, J. L. et al. PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS. J. Med. Chem. 58, 2091-2113 (2015).
25. Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529-533 (2011).
26. Chaidos, A. et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123, 697-705 (2014).
27. Bartholomeeusen, K., Xiang, Y., Fujinaga, K. & Peterlin, B. M. Bromodomain and extra-terminal (BET) bromodomain inhibition activate transcription via transient release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein. J. Biol. Chem. 287, 36609-36616 (2012).
28. Winter, G. E. et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376-1381 (2015).
29. Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755-763 (2015).
30. Zengerle, M., Chan, K. H. & Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10, 1770-1777 (2015).
31. Matzuk, M. M. et al. Small-molecule inhibition of BRDT for male contraception. Cell 150, 673-684 (2012).
32. Dutta Roy, R. & Stefan, M. I. Cooperative binding mitigates the high-dose hook effect. Preprint at. bioRxiv http://dx. doi. org/10. 1101/021717 (2015).
33. Martinez Molina, D. et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84-87 (2013).
34. Arrowsmith, C. H. et al. The promise and peril of chemical probes. Nat. Chem. Biol. 11, 536-541 (2015).
35. Schultz, J., Copley, R. R., Doerks, T., Ponting, C. P. & Bork, P. SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res. 28, 231-234 (2000).
36. Sanchez, R., Meslamani, J. & Zhou, M. M. The bromodomain: from epigenome reader to druggable target. Biochim. Biophys. Acta 1839, 676-685 (2014).
37. Anonymous. Bromosporine. SGC http://www. thesgc. org/chemical-probes/Bromosporine (accessed 19 June 2016).
38. French, C. A. et al. Midline carcinoma of children and young adults with NUT rearrangement. J. Clin. Oncol. 22, 4135-4139 (2004).
39. Anders, L. et al. Genome-wide localization of small molecules. Nat. Biotechnol. 32, 92-96 (2014).
40. Brumatti, G., Sheridan, C. & Martin, S. J. Expression and purification of recombinant annexin V for the detection of membrane alterations on apoptotic cells. Methods 44, 235-240 (2008).
41. Kabsch, W. Integration, scaling, space-group assignment and post-refinement. Acta Crystallogr. D Biol. Crystallogr. 66, 133-144 (2010).
42. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007).
43. Smart, O. S. et al. Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER. Acta Crystallogr. D Biol. Crystallogr. 68, 368-380 (2012).
44. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213-221 (2010).
45. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132 (2004).
46. Wiseman, T., Williston, S., Brandts, J. F. & Lin, L. N. Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal. Biochem. 179, 131-137 (1989).