Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.
作者： Brian K. Albrecht , Victor S. Gehling , Michael C. Hewitt , Rishi G. Vaswani , Alexandre Côté
DOI: 10.1021/ACS.JMEDCHEM.5B01882
关键词: Gene 、 Nuclear protein 、 In vivo 、 Molecular biology 、 Transcription factor 、 Gene expression 、 Proto-Oncogene Proteins c-myc 、 Chromatin 、 Biology 、 Cancer research 、 Bromodomain
摘要: In recent years, inhibition of the interaction between bromodomain and extra-terminal domain (BET) family chromatin adaptors acetyl-lysine residues on has emerged as a promising approach to regulate expression important disease-relevant genes, including MYC, BCL-2, NF-κB. Here we describe identification characterization potent selective benzoisoxazoloazepine BET inhibitor that attenuates BET-dependent gene in vivo, demonstrates antitumor efficacy an MV-4-11 mouse xenograft model, is currently undergoing human clinical trials for hematological malignancies (CPI-0610).
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rcsb.org参考文章(27)
Binyamin D. Berkovits, Debra J. Wolgemuth, The Role of the Double Bromodomain-Containing BET Genes During Mammalian Spermatogenesis Current Topics in Developmental Biology. ,vol. 102, pp. 293- 326 ,(2013) , 10.1016/B978-0-12-416024-8.00011-8
Marie-Magdelaine Coudé, Thorsten Braun, Jeannig Berrou, Mélanie Dupont, Sibyl Bertrand, Aline Masse, Emmanuel Raffoux, Raphaël Itzykson, Marc Delord, Maria E. Riveiro, Patrice Herait, André Baruchel, Hervé Dombret, Claude Gardin, BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells Oncotarget. ,vol. 6, pp. 17698- 17712 ,(2015) , 10.18632/ONCOTARGET.4131
Michael C. Hewitt, Yves Leblanc, Victor S. Gehling, Rishi G. Vaswani, Alexandre Côté, Christopher G. Nasveschuk, Alexander M. Taylor, Jean-Christophe Harmange, James E. Audia, Eneida Pardo, Rich Cummings, Shivangi Joshi, Peter Sandy, Jennifer A. Mertz, Robert J. Sims, Louise Bergeron, Barbara M. Bryant, Steve Bellon, Florence Poy, Hariharan Jayaram, Yong Tang, Brian K. Albrecht, Development of methyl isoxazoleazepines as inhibitors of BET Bioorganic & Medicinal Chemistry Letters. ,vol. 25, pp. 1842- 1848 ,(2015) , 10.1016/J.BMCL.2015.03.045
Mark A. Dawson, Rab K. Prinjha, Antje Dittmann, George Giotopoulos, Marcus Bantscheff, Wai-In Chan, Samuel C. Robson, Chun-wa Chung, Carsten Hopf, Mikhail M. Savitski, Carola Huthmacher, Emma Gudgin, Dave Lugo, Soren Beinke, Trevor D. Chapman, Emma J. Roberts, Peter E. Soden, Kurt R. Auger, Olivier Mirguet, Konstanze Doehner, Ruud Delwel, Alan K. Burnett, Phillip Jeffrey, Gerard Drewes, Kevin Lee, Brian J. P. Huntly, Tony Kouzarides, Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia Nature. ,vol. 478, pp. 529- 533 ,(2011) , 10.1038/NATURE10509
Deanna A. Mele, Andres Salmeron, Srimoyee Ghosh, Hon-Ren Huang, Barbara M. Bryant, Jose M. Lora, BET bromodomain inhibition suppresses TH17-mediated pathology. Journal of Experimental Medicine. ,vol. 210, pp. 2181- 2190 ,(2013) , 10.1084/JEM.20130376
Juan de M. Muñoz, Jesús Alcázar, Antonio de la Hoz, Ángel Díaz-Ortiz, Sergio-A. Alonso de Diego, Preparation of amides mediated by isopropylmagnesium chloride under continuous flow conditions Green Chemistry. ,vol. 14, pp. 1335- 1341 ,(2012) , 10.1039/C2GC35037H
Edwige Nicodeme, Kate L. Jeffrey, Uwe Schaefer, Soren Beinke, Scott Dewell, Chun-wa Chung, Rohit Chandwani, Ivan Marazzi, Paul Wilson, Hervé Coste, Julia White, Jorge Kirilovsky, Charles M. Rice, Jose M. Lora, Rab K. Prinjha, Kevin Lee, Alexander Tarakhovsky, Suppression of inflammation by a synthetic histone mimic Nature. ,vol. 468, pp. 1119- 1123 ,(2010) , 10.1038/NATURE09589
Thomas Ryckmans, Martin P. Edwards, Val A. Horne, Ana Monica Correia, Dafydd R. Owen, Lisa R. Thompson, Isabelle Tran, Michelle F. Tutt, Tim Young, Rapid assessment of a novel series of selective CB2 agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis Bioorganic & Medicinal Chemistry Letters. ,vol. 19, pp. 4406- 4409 ,(2009) , 10.1016/J.BMCL.2009.05.062
Anastasia Wyce, Gopinath Ganji, Kimberly N. Smitheman, Chun-wa Chung, Susan Korenchuk, Yuchen Bai, Olena Barbash, BaoChau Le, Peter D. Craggs, Michael T. McCabe, Karen M. Kennedy-Wilson, Lydia V. Sanchez, Romain L. Gosmini, Nigel Parr, Charles F. McHugh, Dashyant Dhanak, Rab K. Prinjha, Kurt R. Auger, Peter J. Tummino, Bet Inhibition Silences Expression of Mycn and Bcl2 and Induces Cytotoxicity in Neuroblastoma Tumor Models. PLOS ONE. ,vol. 8, pp. 72967- ,(2013) , 10.1371/JOURNAL.PONE.0072967
J. A. Mertz, A. R. Conery, B. M. Bryant, P. Sandy, S. Balasubramanian, D. A. Mele, L. Bergeron, R. J. Sims, Targeting MYC dependence in cancer by inhibiting BET bromodomains Proceedings of the National Academy of Sciences of the United States of America. ,vol. 108, pp. 16669- 16674 ,(2011) , 10.1073/PNAS.1108190108