Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Picaud, S.; Fedorov, O.; Thanasopoulou, Angeliki; Leonards, Katharina; Jones, Katherine L.; Meier, Julia; Olzscha, Heidi; Monteiro, Octovia; Martin, Sarah; Philpott, Martin; Tumber, Anthony; Filippakopoulos, P.; Yapp, Clarence; Wells, Christopher; Hing, Ka; Bannister, Andrew J.; Robson, Samuel; Kumar, Umesh; Parr, Nigel J.; Lee, Kevin; Lugo, Dave; Jeffrey, Philip; Taylor, S.; Vecellio, Matteo; Bountra, C.; Brennan, P.E.; O’Mahony, Alison; Velichko, Sharlene; Müller, Susanne; Hay, Duncan; Daniels, Danette L.; Urh, Marjeta; Thangué, Nicholas B. La; Kouzarides, Tony; Prinjha, Rab K.; Schwaller, Jürg; Knapp, Stefan

doi:10.1158/0008-5472.can-15-0236

Cited by 212 publications

(221 citation statements)

References 49 publications

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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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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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“…1D). We and others have previously shown CBP/p300 bromodomain inhibition to have antitumor activity in hematologic cancer models (31)(32)(33). GNE-049 is a potent inhibitor of both the CBP (IC 50 ¼ 1.1 nmol/L) and p300 (IC 50 ¼ 2.3 nmol/L) bromodomains in a biochemical bromodomainbinding assay (Supplementary Fig.…”

Section: Ar-driven Prostate Cancer Cell Lines Are Sensitive To Cbp/p3mentioning

confidence: 90%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

129

106

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Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castrationresistant prostate cancer. Cancer Res; 77(20); 5564-75. Ó2017 AACR.

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“…The second BD, BD2, selects for acetylated nonhistone proteins, though it is also capable of associating with acetylated histones H3 and H4. In the past few years, a number of BRD4-specific inhibitors have been developed, with some showing therapeutic effects in cancer models for NUT midline carcinoma, multiple myeloma, lymphoid leukemia, myeloid leukemia, and neuroblastoma (7,8,10,12,(18)(19)(20)(21)(22)(23).Because MYC itself has been proven to be a difficult therapeutic target, the PI3K-AKT-mTOR pathway and inhibition of PI3K kinase activity in particular has been a main focus of drug development (4, 24). However, inhibition of PI3K to enhance degradation of MYC provides only a limited therapeutic effect and is often followed by the development of resistance to the drug (25).…”

mentioning

confidence: 99%

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Andrews

Singh

Joshi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

118

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MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dualactivity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.T he MYC gene is frequently altered in human cancer. It encodes a transcription factor that binds to and regulates nearly 10-15% of genes in the human genome (1-3). The MYC targets mediate fundamental biological processes necessary for cell survival and general well-being, ranging from gene-expression and cell-cycle programs to cell proliferation and response to DNA damage, thereby establishing MYC as a global transcriptional regulator. MYC is overexpressed or amplified in many human cancers, which results in genome instability and deregulation of an array of signaling pathways responsible for malignant transformation. MYC expression level as well as synthesis, stability, and posttranslational modifications (PTMs) of the MYC protein are tightly regulated via several pathways, including PI3K-AKTmTOR and RAS-MAPK (4). Particularly, PI3K activation blocks MYC degradation through inhibiting GSK3β-dependent MYC phosphorylation at threonine 58, elevating MYC levels and inducing MYC-dependent oncogenic programs (4, 5).MYC gene expression has recently been linked to the activity of the BET (bromodomains and extraterminal domain) family of transcriptional coactivators (6-9). The BET protein BRD4 is found enriched at MYC and other oncogenes superenhancer and promoter regions, and transcriptional silencing of MYC coincides with the release of BET proteins from its locus, indicating that BET proteins can regulate MYC expression (10, 11). BRD4 itself is linked to multiple human malignancies: It forms chromosomal translocations in squamous carcinoma and NUT midline carcinoma, plays a role in progression of acute myeloid leukemia, and is up-regulated in breast cancer (7,(12)(13)(14). BRD4 contains a pair of bromodomains (BDs) that belong to the family of evolutionarily conserved structural modules that recognize acetyllysine PTMs in histones and nonhistone proteins (15, 16). Interestingly, BD1 and BD2 of BRD4 have distinct acetyllysine binding functions (17). BD1 binds to diacetylated histones, including histone H4 diacetylated at lysine 5 and lysine 8 (H4K5acK8ac), and this interaction helps to recruit or stabilize BRD4-containing transcription complexes at target gene promoters and enhancers. The se...

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Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Cited by 212 publications

References 49 publications

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

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