Journal ArticleDOI
Targeting bromodomains: epigenetic readers of lysine acetylation
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TLDR
Recent progress in the development of bromodomain inhibitors is highlighted, and their potential applications in drug discovery are highlighted.Abstract:
Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.read more
Citations
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Phthalimide conjugation as a strategy for in vivo target protein degradation
Georg E. Winter,Dennis L. Buckley,Joshiawa Paulk,Justin M. Roberts,Amanda Souza,Sirano Dhe-Paganon,James E. Bradner +6 more
TL;DR: In this paper, a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival, was devised.
Journal ArticleDOI
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.
Journal ArticleDOI
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
TL;DR: Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins open up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.
Journal ArticleDOI
The promise and peril of chemical probes.
Cheryl H. Arrowsmith,James E. Audia,Christopher M. Austin,Jonathan B. Baell,Jonathan Bennett,Julian Blagg,C. Bountra,Paul Brennan,Peter Brown,Mark E. Bunnage,Carolyn Buser-Doepner,Robert M. Campbell,Adrian Carter,Philip Cohen,Robert A. Copeland,Ben Cravatt,Jayme L. Dahlin,Dashyant Dhanak,Aled M. Edwards,Mathias Frederiksen,Stephen V. Frye,Nathanael S. Gray,Charles E. Grimshaw,David Hepworth,Trevor Howe,Kilian Huber,Jian Jin,Stefan Knapp,Joanne Kotz,Ryan G. Kruger,Derek B. Lowe,Mary M. Mader,Brian D. Marsden,Anke Mueller-Fahrnow,Susanne Müller,Ronan C. O'Hagan,John P. Overington,Dafydd R. Owen,Saul H Rosenberg,Bryan L. Roth,Ruth A. Ross,Matthieu Schapira,Stuart L. Schreiber,Brian K. Shoichet,Michael Sundström,Giulio Superti-Furga,Jack Taunton,Leticia Toledo-Sherman,Chris Walpole,Michael A. Walters,Timothy M. Willson,Paul Workman,Robert N. Young,William J. Zuercher +53 more
TL;DR: A community-driven wiki resource to improve quality and convey current best practice on chemical probes, and to help address shortcomings of poor quality or that are used incorrectly generate misleading results.
Journal ArticleDOI
PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.
Kanak Raina,Jing Lu,Yimin Qian,Martha Altieri,Deborah M. Gordon,Ann Marie Rossi,Jing Wang,Xin Chen,Hanqing Dong,Kam W. Siu,James D. Winkler,Andrew P. Crew,Craig M. Crews,Kevin Coleman +13 more
TL;DR: This study proves that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition.
References
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Systematic Review: Process of Forming Academic Service Partnerships to Reform Clinical Education
TL;DR: This study’s findings can provide practical guidelines to steer partnership programs within the academic and clinical bodies, with the aim of providing a collaborative partnership approach to clinical education.
Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
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Chromatin Modifications and Their Function
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Journal ArticleDOI
Translating the Histone Code
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Journal ArticleDOI
Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions
Chunaram Choudhary,Chanchal Kumar,Florian Gnad,Michael L. Nielsen,Michael Rehman,Tobias C. Walther,Jesper V. Olsen,Matthias Mann +7 more
TL;DR: A proteomic-scale analysis of protein acetylation suggests that it is an important biological regulatory mechanism and the regulatory scope of lysine acetylations is broad and comparable with that of other major posttranslational modifications.
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