Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation
Omer Gilan,Omer Gilan,Inmaculada Rioja,Kathy Knezevic,Matthew J Bell,Miriam M. Yeung,Nicola Harker,Enid Y.N. Lam,Enid Y.N. Lam,Chun-wa Chung,Paul Bamborough,Massimo Petretich,Marjeta Urh,Stephen John Atkinson,Anna K. Bassil,Emma J. Roberts,Dane Vassiliadis,Dane Vassiliadis,Marian L. Burr,Marian L. Burr,Alex Preston,Christopher Roland Wellaway,Thilo Werner,James Gray,Anne Marie Michon,Thomas Gobbetti,Vinod Kumar,Peter Ernest Soden,Andrea C. Haynes,Johanna Vappiani,David F. Tough,Simon Taylor,Sarah-Jane Dawson,Sarah-Jane Dawson,Marcus Bantscheff,Matthew J Lindon,Gerard Drewes,Emmanuel Hubert Demont,Danette L. Daniels,Paola Grandi,Rab K. Prinjha,Mark A. Dawson,Mark A. Dawson +42 more
TLDR
It is found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins, which may guide future BET-targeted therapies.Abstract:
The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.read more
Citations
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Achieving clinical success with BET inhibitors as anti-cancer agents.
TL;DR: In this paper, the authors discuss the biology of BET proteins, advances in BETi design and highlight potential biomarkers predicting their activity, and suggest that understanding mechanisms of activity, defining predictive biomarkers and identifying potent synergies represents a roadmap for clinical success using BETi.
Journal ArticleDOI
The BET family in immunity and disease
TL;DR: The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3 and BRD4) that regulate the expression of many immunity-associated genes and pathways.
Journal ArticleDOI
BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.
Richard J. Mills,Sean J. Humphrey,Patrick R. J. Fortuna,Mary Lor,Simon R. Foster,Gregory A. Quaife-Ryan,Rebecca L Johnston,Troy Dumenil,Cameron Bishop,Rajeev Rudraraju,Daniel J. Rawle,Thuy T. Le,Wei Zhao,Leo J. Lee,Charley Mackenzie-Kludas,Neda R Mehdiabadi,Christopher Halliday,Dean Gilham,Li Fu,Stephen J. Nicholls,Jan Johansson,Michael O. Sweeney,Norman C.W. Wong,Ewelina Kulikowski,Kamil A. Sokolowski,Brian W.C. Tse,Lynn Devilee,Holly K. Voges,Liam T Reynolds,Sophie Krumeich,Ellen Mathieson,Dad Abu-Bonsrah,Dad Abu-Bonsrah,Kathy Karavendzas,Brendan Griffen,Drew M. Titmarsh,David A. Elliott,James H McMahon,James H McMahon,Andreas Suhrbier,Kanta Subbarao,Enzo R. Porrello,Enzo R. Porrello,Mark J. Smyth,Christian R. Engwerda,Kelli P. A. MacDonald,Tobias Bald,Tobias Bald,David E. James,James E. Hudson +49 more
TL;DR: In this paper, a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing was used to identify mechanisms and cardio-protective drugs.
Journal ArticleDOI
Advances in targeting ‘undruggable’ transcription factors with small molecules
TL;DR: In this article, a review of TF-mediated gene regulation, discuss successful targeting strategies and highlight ongoing challenges and emerging approaches to address them, as well as several emerging approaches for TF-targeting.
Journal ArticleDOI
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity.
Satomi Imaide,Kristin M. Riching,Nikolai Makukhin,Vesna Vetma,Claire Whitworth,Scott J. Hughes,Nicole Trainor,Sarah D. Mahan,Nancy Murphy,Angus D. Cowan,Kwok-Ho Chan,Kwok-Ho Chan,Conner Craigon,Andrea Testa,Chiara Maniaci,Chiara Maniaci,Marjeta Urh,Danette L. Daniels,Alessio Ciulli +18 more
TL;DR: In this paper, a trivalent PROTAC consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker was designed.
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BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
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Leslie van der Fits,Sabine Mourits,Jane S. A. Voerman,Marius Kant,Louis Boon,Jon D. Laman,Ferry Cornelissen,Anne-Marie Mus,Edwin Florencia,Errol P. Prens,Erik Lubberts +10 more
TL;DR: The sole application of the innate TLR7/8 ligand IMQ rapidly induces a dermatitis closely resembling human psoriasis, critically dependent on the IL-23/IL-17 axis.
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