Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

Conery, Andrew R.; Centore, Richard C.; Neiss, Adrianne; Keller, Patricia J.; Joshi, Shivangi; Spillane, Kerry L.; Sandy, Péter; Hatton, Charlie; Pardo, Eneida; Zawadzke, Laura E.; Bommi-Reddy, Archana; Gascoigne, Karen E.; Bryant, Barbara M.; Mertz, Jennifer A.; Sims, Robert J.

doi:10.7554/elife.10483

Cited by 82 publications

(105 citation statements)

References 36 publications

(65 reference statements)

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“…Indeed, it has been reported previously 3,32 and we confirm here that I-CBP112 does have antiproliferative action against cancer. The significant inhibition of proliferation could be a result of stimulation of p300/CBP HAT activity on nucleosomes, as observed in this study, or perhaps though modulation of p300 acetylation of non-histone substrates or other protein–protein interaction functions.…”

Section: Discussionsupporting

confidence: 91%

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

Zucconi

Luef

et al. 2016

Biochemistry

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The histone acetyltransferase (HAT) enzymes p300 and CBP are closely related paralogs that serve as transcriptional coactivators and have been found to be dysregulated in cancer and other diseases. p300/CBP is a multidomain protein and possesses a highly conserved bromodomain that has been shown to bind acetylated Lys residues in both proteins and various small molecules, including I-CBP112 and CBP30. Here we show that the ligand I-CBP112 can stimulate nucleosome acetylation up to 3-fold while CBP30 does not. Activation of p300/CBP by I-CBP112 is not observed with the isolated histone H3 substrate but requires a nucleosome substrate. I-CBP112 does not impact nucleosome acetylation by the isolated p300 HAT domain, and the effects of I-CBP112 on p300/CBP can be neutralized by CBP30, suggesting that I-CBP112 likely allosterically activates p300/CBP through bromodomain interactions. Using mass spectrometry and Western blots, we have found that I-CBP112 particularly stimulates acetylation of Lys18 of histone H3 (H3K18) in nucleosomes, an established in vivo site of p300/CBP. In addition, we show that I-CBP112 enhances H3K18 acetylation in acute leukemia and prostate cancer cells in a concentration range commensurate with its antiproliferative effects. Our findings extend the known pharmacology of bromodomain ligands in the regulation of p300/CBP and suggest a novel approach to modulating histone acetylation in cancer.

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Section: Discussionsupporting

confidence: 91%

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

Zucconi

Luef

et al. 2016

Biochemistry

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“…We did not, however, observe a global expulsion of EP300 from chromatin as a consequence of bromodomain inhibition, either in Tregs or in other cellular contexts (data not shown). These results are consistent with recent publications exploring the function of CBP/EP300 bromodomain inhibition in cancer cell line contexts (32,33). The most prevalent functional effect of CBP/EP300 bromodomain inhibition was reduced acetylation of H3K18 and H3K27 (and other proteins; see below).…”

Section: Cbp/ep300 Bromodomain Inhibition Alters the Human Tregsupporting

confidence: 92%

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition

Ghosh

Taylor

Chin

et al. 2016

Journal of Biological Chemistry

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Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/ EP300 bromodomain inhibition as a novel, small moleculebased approach for cancer immunotherapy.

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“…Recently, we have reported that the bromodomain of CBP/EP300 regulates MYC, a transcription factor widely expressed in human cancer. 33 In a cellular assay, we found that 28 inhibits the expression of MYC with an EC 50 of 0.60 μM, providing an orthogonal measure of the target engagement of the compound (Figure 3). In our hands, the reported CBP bromodomain inhibitors I-CBP112 and SGC-CBP30 demonstrated EC 50 values of >20 and 2.7 μM, respectively.…”

mentioning

confidence: 98%

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

Taylor

Côté

Hewitt

et al. 2016

ACS Med. Chem. Lett.

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CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo [b][1,4]diazepin-2-one.

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Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

Cited by 82 publications

References 36 publications

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

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