Literature DB >> 24900758

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.

Victor S Gehling1, Michael C Hewitt1, Rishi G Vaswani1, Yves Leblanc1, Alexandre Côté1, Christopher G Nasveschuk1, Alexander M Taylor1, Jean-Christophe Harmange1, James E Audia1, Eneida Pardo1, Shivangi Joshi1, Peter Sandy1, Jennifer A Mertz1, Robert J Sims1, Louise Bergeron1, Barbara M Bryant1, Steve Bellon1, Florence Poy1, Hariharan Jayaram1, Ravichandran Sankaranarayanan2, Sreegouri Yellapantula2, Nandana Bangalore Srinivasamurthy2, Swarnakumari Birudukota2, Brian K Albrecht1.   

Abstract

The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.

Entities:  

Keywords:  BET inhibitors; MYC; bromodomain; fragments; isoxazoles

Year:  2013        PMID： 24900758      PMCID： PMC4027525          DOI： 10.1021/ml4001485

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  23 in total

1.  Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery.

Authors:  Chun-Wa Chung; Anthony W Dean; James M Woolven; Paul Bamborough
Journal:  J Med Chem       Date:  2012-01-11       Impact factor: 7.446

2.  From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151.

Authors:  Olivier Mirguet; Yann Lamotte; Frédéric Donche; Jérôme Toum; Françoise Gellibert; Anne Bouillot; Romain Gosmini; Van-Loc Nguyen; Delphine Delannée; Jonathan Seal; Florence Blandel; Anne-Bénédicte Boullay; Eric Boursier; Sandrine Martin; Jean-Marie Brusq; Gael Krysa; Alizon Riou; Rémi Tellier; Agnès Costaz; Pascal Huet; Yann Dudit; Lionel Trottet; Jorge Kirilovsky; Edwige Nicodeme
Journal:  Bioorg Med Chem Lett       Date:  2012-02-08       Impact factor: 2.823

3.  An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs.

Authors:  Emanuele Perola
Journal:  J Med Chem       Date:  2010-04-08       Impact factor: 7.446

4.  BET bromodomain inhibition as a therapeutic strategy to target c-Myc.

Authors:  Jake E Delmore; Ghayas C Issa; Madeleine E Lemieux; Peter B Rahl; Junwei Shi; Hannah M Jacobs; Efstathios Kastritis; Timothy Gilpatrick; Ronald M Paranal; Jun Qi; Marta Chesi; Anna C Schinzel; Michael R McKeown; Timothy P Heffernan; Christopher R Vakoc; P Leif Bergsagel; Irene M Ghobrial; Paul G Richardson; Richard A Young; William C Hahn; Kenneth C Anderson; Andrew L Kung; James E Bradner; Constantine S Mitsiades
Journal:  Cell       Date:  2011-09-01       Impact factor: 41.582

5.  Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides.

Authors:  Paul Bamborough; Hawa Diallo; Jonathan D Goodacre; Laurie Gordon; Antonia Lewis; Jonathan T Seal; David M Wilson; Michael D Woodrow; Chun-Wa Chung
Journal:  J Med Chem       Date:  2012-01-11       Impact factor: 7.446

Review 6.  The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation.

Authors:  Shwu-Yuan Wu; Cheng-Ming Chiang
Journal:  J Biol Chem       Date:  2007-02-28       Impact factor: 5.157

7.  Suppression of inflammation by a synthetic histone mimic.

Authors:  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
Journal:  Nature       Date:  2010-11-10       Impact factor: 49.962

8.  Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain.

Authors:  Lele Zhao; Danyan Cao; Tiantian Chen; Yingqing Wang; Zehong Miao; Yechun Xu; Wuyan Chen; Xin Wang; Yanlian Li; Zhiyan Du; Bing Xiong; Jian Li; Chunyan Xu; Naixia Zhang; Jianhua He; Jingkang Shen
Journal:  J Med Chem       Date:  2013-05-14       Impact factor: 7.446

9.  Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

Authors:  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
Journal:  Nature       Date:  2011-10-02       Impact factor: 49.962

10.  Selective inhibition of BET bromodomains.

Authors:  Panagis Filippakopoulos; Jun Qi; Sarah Picaud; Yao Shen; William B Smith; Oleg Fedorov; Elizabeth M Morse; Tracey Keates; Tyler T Hickman; Ildiko Felletar; Martin Philpott; Shonagh Munro; Michael R McKeown; Yuchuan Wang; Amanda L Christie; Nathan West; Michael J Cameron; Brian Schwartz; Tom D Heightman; Nicholas La Thangue; Christopher A French; Olaf Wiest; Andrew L Kung; Stefan Knapp; James E Bradner
Journal:  Nature       Date:  2010-09-24       Impact factor: 49.962
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  25 in total

Review 1.  The bromodomain: from epigenome reader to druggable target.

Authors:  Roberto Sanchez; Jamel Meslamani; Ming-Ming Zhou
Journal:  Biochim Biophys Acta       Date:  2014-03-28

Review 2.  Targeting bromodomains: epigenetic readers of lysine acetylation.

Authors:  Panagis Filippakopoulos; Stefan Knapp
Journal:  Nat Rev Drug Discov       Date:  2014-04-22       Impact factor: 84.694

Review 3.  BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer.

Authors:  Dequina A Nicholas; Guillaume Andrieu; Katherine J Strissel; Barbara S Nikolajczyk; Gerald V Denis
Journal:  Cell Mol Life Sci       Date:  2016-08-04       Impact factor: 9.261

Review 4.  Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.

Authors:  Michelle R Arkin; Yinyan Tang; James A Wells
Journal:  Chem Biol       Date:  2014-09-18

5.  Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors.

Authors:  Angela S Carlson; Huarui Cui; Anand Divakaran; Jorden A Johnson; Ryan M Brunner; William C K Pomerantz; Joseph J Topczewski
Journal:  ACS Med Chem Lett       Date:  2019-08-02       Impact factor: 4.345

6.  Selective Inhibition of CBX6: A Methyllysine Reader Protein in the Polycomb Family.

Authors:  Natalia Milosevich; Michael C Gignac; James McFarlane; Chakravarthi Simhadri; Shanti Horvath; Kevin D Daze; Caitlin S Croft; Aman Dheri; Taylor T H Quon; Sarah F Douglas; Jeremy E Wulff; Irina Paci; Fraser Hof
Journal:  ACS Med Chem Lett       Date:  2015-12-07       Impact factor: 4.345

Review 7.  Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases.

Authors:  Balasundaram Padmanabhan; Shruti Mathur; Ramu Manjula; Shailesh Tripathi
Journal:  J Biosci       Date:  2016-06       Impact factor: 1.826

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

Authors:  Alexander M Taylor; Rishi G Vaswani; Victor S Gehling; Michael C Hewitt; Yves Leblanc; James E Audia; Steve Bellon; Richard T Cummings; Alexandre Côté; Jean-Christophe Harmange; Hari Jayaram; Shivangi Joshi; Jose M Lora; Jennifer A Mertz; Adrianne Neiss; Eneida Pardo; Christopher G Nasveschuk; Florence Poy; Peter Sandy; Jeremy W Setser; Robert J Sims; Yong Tang; Brian K Albrecht
Journal:  ACS Med Chem Lett       Date:  2015-03-25       Impact factor: 4.345

9.  Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors.

Authors:  Phillip P Sharp; Jean-Marc Garnier; Tamas Hatfaludi; Zhen Xu; David Segal; Kate E Jarman; Hélène Jousset; Alexandra Garnham; John T Feutrill; Anthony Cuzzupe; Peter Hall; Scott Taylor; Carl R Walkley; Dean Tyler; Mark A Dawson; Peter Czabotar; Andrew F Wilks; Stefan Glaser; David C S Huang; Christopher J Burns
Journal:  ACS Med Chem Lett       Date:  2017-11-14       Impact factor: 4.345

Review 10.  Privileged diazepine compounds and their emergence as bromodomain inhibitors.

Authors:  Steven G Smith; Roberto Sanchez; Ming-Ming Zhou
Journal:  Chem Biol       Date:  2014-04-17
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