Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Loren M. Lasko,Clarissa G. Jakob,Rohinton Edalji,Wei Qiu,Debra Montgomery,Enrico L. Digiammarino,T. Matt Hansen,Roberto M. Risi,Robin R. Frey,Vlasios Manaves,Bailin Shaw,Mikkel Algire,Paul Hessler,Lloyd T. Lam,Tamar Uziel,Emily J. Faivre,Debra Ferguson,Fritz G. Buchanan,Ruth L. Martin,Maricel Torrent,Gary G. Chiang,Kannan R. Karukurichi,J. William Langston,Brian T. Weinert,Chunaram Choudhary,Peter de Vries,John H. Van Drie,David L. McElligott,Kesicki Edward A,Ronen Marmorstein,Chaohong Sun,Philip A. Cole,Saul H. Rosenberg,Michael R. Michaelides,Albert Lai,Kenneth D. Bromberg +35 more
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TLDR
The results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.Abstract:
The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 A) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.read more
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Functions and mechanisms of non-histone protein acetylation
TL;DR: Recent progress is discussed in the understanding of the scope, functional diversity and mechanisms of non-histone protein acetylation, which regulates many cellular processes, such as transcription, DNA repair, signal transduction, protein folding and autophagy.
Journal ArticleDOI
Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential
TL;DR: Current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans are described and it is anticipated that CRMs will become part of the pharmacological armamentarium against aging and age-related cardiovascular, neurodegenerative, and malignant diseases.
Journal ArticleDOI
Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome
Brian T. Weinert,Takeo Narita,Shankha Satpathy,Balaji Srinivasan,Bogi Karbech Hansen,Christian Schölz,William B. Hamilton,Beth E. Zucconi,Wesley W. Wang,Wenshe R. Liu,Joshua M. Brickman,Kesicki Edward A,Albert Lai,Kenneth D. Bromberg,Philip A. Cole,Chunaram Choudhary +15 more
TL;DR: This work combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates, revealing a dynamic balance between acetylations and deacetylation.
Journal ArticleDOI
Epigenetic modifications of histones in cancer
Zibo Zhao,Ali Shilatifard +1 more
TL;DR: The enzymatic machineries and modifications that are involved in cancer development and progression are reviewed, and how to apply currently available small molecule inhibitors for histone modifiers as tool compounds to study the functional significance of histone modifications and their clinical implications is reviewed.
Journal ArticleDOI
Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27 Acetylation.
Ryan Raisner,Samir Kharbanda,Lingyan Jin,Edwin E. Jeng,Emily Chan,Mark Merchant,Peter M. Haverty,Russell Bainer,Tommy K. Cheung,David Arnott,E. Megan Flynn,F. Anthony Romero,Steven Magnuson,Karen E. Gascoigne +13 more
TL;DR: A chemical genetics approach is used to acutely block the function of the cAMP response element binding protein (CREB) binding protein (CBP)/P300 bromodomain in models of hematological malignancies and describes a consequent loss of H3K27Ac specifically from enhancers, despite the continued presence of CBP/P300 at chromatin.
References
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Super-Enhancers in the Control of Cell Identity and Disease
Denes Hnisz,Brian J. Abraham,Tong Ihn Lee,Ashley Lau,Violaine Saint-André,Alla A. Sigova,Heather A. Hoke,Richard A. Young +7 more
TL;DR: The super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that define cell identity and play key roles in human cell identity in health and in disease as mentioned in this paper.
Journal ArticleDOI
Histone core modifications regulating nucleosome structure and dynamics
Peter Tessarz,Tony Kouzarides +1 more
TL;DR: Acetylation, methylation, phosphorylation and citrullination of the histone core may influence chromatin structure by affecting histone–histone and hist one–DNA interactions, as well as the binding of histones to chaperones.
Journal ArticleDOI
Distinct roles of GCN5/PCAF‐mediated H3K9ac and CBP/p300‐mediated H3K18/27ac in nuclear receptor transactivation
Qihuang Jin,Li Rong Yu,Lifeng Wang,Zhijing Zhang,Lawryn H. Kasper,Ji-Eun Lee,Chaochen Wang,Paul K. Brindle,Sharon Y.R. Dent,Kai Ge +9 more
TL;DR: The results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF‐ and CBP/p300‐mediated histone acetylations in gene activation, and suggest an important role of CBP/(p300)‐mediated H3K18/27ac in NR‐dependent transcription.
Journal ArticleDOI
p300/CBP and cancer.
TL;DR: A mouse model confirms that p300 and CBP function as suppressors of hematological tumor formation and provides a mechanistic route as to how their inactivation could result in cancer.
Journal ArticleDOI
Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor.
Erin M. Bowers,Gai Yan,Chandrani Mukherjee,Andrew Orry,Ling Wang,Marc A. Holbert,Nicholas T. Crump,Catherine A. Hazzalin,Glen Liszczak,Hua Yuan,Cecilia A. Larocca,S. Adrian Saldanha,Ruben Abagyan,Yan Sun,David J. Meyers,Ronen Marmorstein,Ronen Marmorstein,Louis C. Mahadevan,Rhoda M. Alani,Philip A. Cole +19 more
TL;DR: Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.
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