Journal ArticleDOI
Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors.
Jonathan Thomas Seal,Stephen John Atkinson,Paul Bamborough,Anna K. Bassil,Chun-wa Chung,James J. Foley,Laurie J. Gordon,Paola Grandi,James Gray,Lee Andrew Harrison,Ryan G. Kruger,Jeanne J. Matteo,Michael T. McCabe,Cassie Messenger,Darren Jason Mitchell,Alex Phillipou,Alex Preston,Rab K. Prinjha,Francesco Rianjongdee,Inmaculada Rioja,Simon Taylor,Ian D. Wall,Robert J. Watson,James Michael Woolven,Anastasia Wyce,Xi-Ping Zhang,Emmanuel Hubert Demont +26 more
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TLDR
In this paper, the authors reveal the identification of potent and selective drug-like pan-BD2 inhibitors, such as pyrazole 23 (GSK809) and furan 24(GSK743), derived from the pyrrole fragment 6.Abstract:
The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.read more
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Journal ArticleDOI
Targeting bromodomain-containing proteins: research advances of drug discovery
Zhaoping Pan,Yuxi Zhao,Xiaoyun Wang,Xin Xie,Mingxia Liu,Kaiyao Zhang,Lian Wang,Ding Bai,Leonard J. Foster,Rui Shu,Gu He +10 more
TL;DR: A comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BPs and therapeutic potentials of these drugs is provided in this article .
Journal ArticleDOI
Bromodomain inhibitors and therapeutic applications.
TL;DR: In this paper , the authors highlight the current development of new-generation small molecule inhibitors for the BET and non-BET proteins and discuss the research strategies used to target different bromodomain proteins for a wide array of human diseases including cancers and inflammatory disorders.
Journal ArticleDOI
Virtual Special Issue: Epigenetics 2022.
Courtney C. Aldrich,Félix Calderón,Stuart J. Conway,Chuan He,Jacob M Hooker,Donna M. Huryn,Craig W. Lindsley,Dennis C. Liotta,Christa E. Müller +8 more
TL;DR: The Altmetric Attention Score as mentioned in this paper is a quantitative measure of the attention that a research article has received online, and it is calculated using a weighted average of the number of articles that have been published in the last few days.
Journal ArticleDOI
Virtual Special Issue: Epigenetics 2022.
Courtney C. Aldrich,Félix Calderón,Stuart J. Conway,Chuan He,Jacob M Hooker,Donna M. Huryn,Craig W. Lindsley,Dennis C. Liotta,Christa E. Müller +8 more
TL;DR: The Altmetric Attention Score as discussed by the authors is a quantitative measure of the attention that a research article has received online, and it is calculated using a weighted average of the number of articles that have been published in the last few days.
References
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TL;DR: This review will discuss the biological processes and the structure and function of CCL2, one of the key chemokines that regulate migration and infiltration of monocytes/macrophages.
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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.
Journal ArticleDOI
Functions of bromodomain-containing proteins and their roles in homeostasis and cancer
TL;DR: Bromodomains can be targeted by small-molecule inhibitors, which has stimulated many translational research projects that seek to attenuate the aberrant functions of BRD-containing proteins in disease.
Journal ArticleDOI
Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains.
Chun-wa Chung,Hervé Coste,Julia H. White,Olivier Mirguet,Jonathan I. Wilde,Romain Luc Marie Gosmini,Chris J. Delves,Sylvie M. Magny,Robert Woodward,Stephen A. Hughes,Eric Boursier,Helen R. Flynn,Anne Marie Jeanne Bouillot,Paul Bamborough,Jean-Marie Brusq,Françoise Gellibert,Emma J. Jones,Alizon M. Riou,Paul Homes,Sandrine Martin,Iain Uings,Jérôme Toum,Catherine A. Clément,Anne-Benedicte Boullay,Rachel Grimley,Florence Blandel,Rab K. Prinjha,Kevin Lee,Jorge Kirilovsky,Edwige Nicodeme +29 more
TL;DR: X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.
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Target validation using chemical probes
TL;DR: By developing a 'chemical probe tool kit', and a framework for its use, chemical biology can have a more central role in identifying targets of potential relevance to disease, avoiding many of the biases that complicate target validation as practiced currently.
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