Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors
Victor S. Gehling,Michael C. Hewitt,Rishi G. Vaswani,Yves Leblanc,Alexandre Côté,Christopher G. Nasveschuk,Alexander M. Taylor,Jean-Christophe Harmange,James E. Audia,Eneida Pardo,Shivangi Joshi,Peter Sandy,Jennifer A. Mertz,Robert J. Sims,Louise Bergeron,Barbara M. Bryant,Steve Bellon,Florence Poy,Hariharan Jayaram,Ravichandran Sankaranarayanan,Sreegouri Yellapantula,Nandana Bangalore Srinivasamurthy,Swarnakumari Birudukota,Brian K. Albrecht +23 more
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TLDR
A structure-based drug design effort lead to a novel isoxazole azepine scaffold that showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.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.read more
Citations
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Targeting bromodomains: epigenetic readers of lysine acetylation
TL;DR: Recent progress in the development of bromodomain inhibitors is highlighted, and their potential applications in drug discovery are highlighted.
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Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.
TL;DR: The past 20 years have seen many advances in understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets.
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Targeting transcription factors in cancer - from undruggable to reality.
TL;DR: This Review discusses the various approaches that are being explored to target transcription factors in cancer, with many of the inhibitors developed from such approaches now advancing to early clinical trials.
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Drug Discovery Targeting Bromodomain-Containing Protein 4.
TL;DR: The advances in drug discovery and development of BRD4 inhibitors are summarized by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential.
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Bromodomains: Structure, function and pharmacology of inhibition.
TL;DR: An updated view of the structure and function of bromodomains is presented, the development of bRomodomain inhibitors and their potential therapeutic applications are traced, and the current challenges and future directions of this vibrant new field in drug discovery are surveyed.
References
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Journal ArticleDOI
Selective inhibition of BET bromodomains.
Panagis Filippakopoulos,Jun Qi,Sarah Picaud,Yao Shen,William B. Smith,Oleg Fedorov,Elizabeth M. Morse,T. Keates,Tyler T. Hickman,I. Felletar,Martin Philpott,Shonagh Munro,Michael R. McKeown,Yuchuan Wang,Amanda L. Christie,Nathan West,Michael J. Cameron,Brian E. Schwartz,Tom D. Heightman,Nicholas B. La Thangue,Christopher A. French,Olaf Wiest,Andrew L. Kung,Stefan Knapp,Stefan Knapp,James E. Bradner +25 more
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Journal ArticleDOI
BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake 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,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more
TL;DR: In this paper, a small-molecule bromodomain inhibitor, JQ1, was used to identify BET proteins as regulatory factors for c-Myc oncoprotein.
Journal ArticleDOI
Suppression of inflammation by a synthetic histone mimic
Edwige Nicodeme,Kate L. Jeffrey,Uwe Schaefer,Soren Beinke,Scott Dewell,Chun-wa Chung,Rohit Chandwani,Ivan Marazzi,Paul A. Wilson,Hervé Coste,Julia H. White,Jorge Kirilovsky,Charles M. Rice,Jose M. Lora,Rab K. Prinjha,Kevin Lee,Alexander Tarakhovsky +16 more
TL;DR: A synthetic compound (I-BET) is described that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis.
Journal ArticleDOI
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia
Mark A. Dawson,Rab K. Prinjha,Antje Dittmann,George Giotopoulos,Marcus Bantscheff,Wai-In Chan,Samuel Robson,Chun-wa Chung,Carsten Hopf,Mikhail M. Savitski,Carola Huthmacher,Emma Gudgin,Dave Lugo,Soren Beinke,Trevor D. Chapman,Emma J. Roberts,Peter Ernest Soden,Kurt R. Auger,Olivier Mirguet,Konstanze Doehner,Ruud Delwel,Alan Kenneth Burnett,Phillip Jeffrey,Gerard Drewes,Kevin Lee,Brian J. P. Huntly,Tony Kouzarides +26 more
TL;DR: It is shown that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis, establishing the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
Journal ArticleDOI
Targeting MYC dependence in cancer by inhibiting BET bromodomains
Jennifer A. Mertz,Andrew R. Conery,Barbara M. Bryant,Peter Sandy,Srividya Balasubramanian,Deanna A. Mele,Louise Bergeron,Robert J. Sims +7 more
TL;DR: It is demonstrated that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and such inhibitors may have clinical utility given the widespread pathogenetic role of MyC in cancer.
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