Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

ACS Medicinal Chemistry Letters

Volumn 7, Issue 2, 2016, Pages 145-150

  Taylor, Alexander M ^a   Vaswani, Rishi G ^a   Gehling, Victor S ^a   Hewitt, Michael C ^a   Leblanc, Yves ^a   Audia, James E ^a   Bellon, Steve ^a   Cummings, Richard T ^a   Coîté, Alexandre ^a   Harmange, Jean Christophe ^a   Jayaram, Hari ^a,b   Joshi, Shivangi ^a   Lora, Jose M ^a   Mertz, Jennifer A ^a   Neiss, Adrianne ^a   Pardo, Eneida ^a   Nasveschuk, Christopher G ^a   Poy, Florence ^a   Sandy, Peter ^a   Setser, Jeremy W ^a   Sims, Robert J ^a   Tang, Yong ^a   Albrecht, Brian K ^a   more..

^a Department of Structural Biology   (United States)

^b EDITAS MEDICINE   (United States)

Author keywords

BET; BRD4; Bromodomain; IL 6 inhibition

Indexed keywords

AZEPINE DERIVATIVE; BENZOTRIAZOLO[4,3 D][1,4]DIAZEPINE; BENZ[B]ISOXAZOL[4,5 D]AZEPINE; BROMODOMAIN INHIBITOR; DIAZEPINE DERIVATIVE; INTERLEUKIN 6; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG POTENCY; DRUG SELECTIVITY; LIVER MICROSOME; METABOLIC STABILITY; MOUSE; NONHUMAN; PHARMACODYNAMICS; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; RAT; STRUCTURE ACTIVITY RELATION;

EID: 84958978363     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml500411h     Document Type: Article

References (18)

1. Wu, S. Y.; Chiang, C. M. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation J. Biol. Chem. 2007, 282, 13141-45
2. Dey, A.; Chitsaz, F.; Abbasi, A.; Misteli, T.; Ozato, K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 8758-63
3. Miyoshi, M.; Ooike, S.; Iwata, K.; Hikawa, H.; Sugahara, K. Antitumor Compounds. WO 2009/084693A1, published Sept. 9, 2009.
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, 1067-73
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, 1119-23
6. Belkina, A. C.; Denis, G. V. BET domain co-regulators in obesity, inflammation and cancer Nat. Rev. Cancer 2012, 12, 465-77
7. Mertz, J. A.; Conery, A. R.; Bryant, B. M.; Sandy, P.; Balasubramanian, S.; Mele, D. A.; Bergeron, L.; Sims, R. J., 3rd Targeting MYC dependence in cancer by inhibiting BET bromodomains Proc. Nat. Acad. Sci. 2011, 108, 16669-74
8. Zuber, J.; Shi, J.; Wang, E.; Rappaport, A. R.; Herrmann, H.; Sison, E. A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M.; Taylor, M. J.; Johns, C.; Chicas, A.; Mulloy, J. C.; Kogan, S. C.; Brown, P.; Valent, P.; Bradner, J. E.; Lowe, S. W.; Vakoc, C. R. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia Nature 2011, 478, 524-8
9. Shi, J.; Vakoc, C. R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition Mol. Cell 2014, 54, 728-36
10. Mele, D. A.; Salmeron, A.; Ghosh, S.; Huang, H. R.; Bryant, B. M.; Lora, J. M. BET bromodomain inhibition suppresses TH17-mediated pathology J. Exp. Med. 2013, 210, 2181-90
11. Khan, Y. M.; Kirkham, P.; Barnes, P. J.; Adcock, I. M. Brd4 is essential for IL-1β-induced inflammation in human airway epithelial cells PLoS One 2014, 9, e95051
12. Gehling, V. S.; Hewitt, M. C.; Vaswani, R. G.; Leblanc, Y.; Coîté, A.; Nasveschuk, C. G.; Taylor, A. M.; Harmange, J. C.; Audia, J. E.; Pardo, E.; Joshi, S.; Sandy, P.; Mertz, J. A.; Sims, R. J., 3rd; Bergeron, L.; Bryant, B. M.; Bellon, S.; Poy, F.; Jayaram, H.; Sankaranarayanan, R.; Yellapantula, S.; Bangalore Srinivasamurthy, N.; Birudukota, S.; Albrecht, B. K. Discovery, design, and optimization of isoxazole azepine BET inhibitors ACS Med. Chem. Lett. 2013, 4, 835-40
13. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 2002, 45, 2615-23
14. Bogdan, A. R.; Davies, N. L.; James, K. Comparison of diffusion coefficients for matched pairs of macrocyclic and linear molecules over a drug-like molecular weight range Org. Biomol. Chem. 2011, 9, 7727-33
15. Horowitz, S.; Trievel, R. C. Carbon-oxygen hydrogen bonding in biological structure and function J. Biol. Chem. 2012, 287, 41576-82
16. Bissantz, C.; Kuhn, B.; Stahl, M. A Medicinal Chemist's Guide to Molecular Interactions J. Med. Chem. 2010, 53, 5061-84
17. Muller, S.; Filippakopoulos, P.; Knapp, S. Bromodomains as therapeutic targets Expert Rev. Mol. Med. 2011, 13, e29
18. Smith, D. A.; Di, L.; Kerns, E. H. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery Nat. Rev. Drug Discovery 2010, 9, 929-39