Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

Hewings, David S.; Rooney, Timothy P. C.; Jennings, Laura E.; Hay, Duncan; Schofield, Christopher J.; Brennan, P.E.; Knapp, Stefan; Conway, Stuart J.

doi:10.1021/jm300915b

Cited by 166 publications

(187 citation statements)

References 85 publications

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“…BET proteins, and Brd4 in particular, have attracted intense interest because of their pleiotropic functions in a range of human diseases (40). Most of this effort has been focused on selectively targeting the bromodomains of BET proteins with mimics of acetylated lysine to prevent their association with chromatin (41)(42)(43). We show that a peptide comprising the EBM can compete with the transcription factor NSD3 for binding to full-length Brd4, highlighting the importance of the ET domain in the interaction.…”

Section: Discussionmentioning

confidence: 99%

“…MLV-based vectors have been curatively used in human gene therapy for treatment of several genetic deficiencies, including X-linked severe combined immune deficiency, Wiscott-Aldrich syndrome, and X-linked chronic granulomatous disease (36)(37)(38)(39)(40). However, a common feature of all of these studies is that a significant number of patients subsequently developed leukemia due to transcriptional up-regulation of protooncogenes (41)(42)(43). Because BET proteins are the primary determinants of MLV integration-site selection (6), structural characterization of the ET-EBM complex allows us to better understand the mechanisms of γ-retroviral integration site selectivity.…”

Section: Discussionmentioning

confidence: 99%

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Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction

Crowe

Larue

Yuan

et al. 2016

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

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The bromodomain and extraterminal domain (BET) protein family are promising therapeutic targets for a range of diseases linked to transcriptional activation, cancer, viral latency, and viral integration. Tandem bromodomains selectively tether BET proteins to chromatin by engaging cognate acetylated histone marks, and the extraterminal (ET) domain is the focal point for recruiting a range of cellular and viral proteins. BET proteins guide γ-retroviral integration to transcription start sites and enhancers through bimodal interaction with chromatin and the γ-retroviral integrase (IN). We report the NMR-derived solution structure of the Brd4 ET domain bound to a conserved peptide sequence from the C terminus of murine leukemia virus (MLV) IN. The complex reveals a proteinprotein interaction governed by the binding-coupled folding of disordered regions in both interacting partners to form a wellstructured intermolecular three-stranded β sheet. In addition, we show that a peptide comprising the ET binding motif (EBM) of MLV IN can disrupt the cognate interaction of Brd4 with NSD3, and that substitutions of Brd4 ET residues essential for binding MLV IN also impair interaction of Brd4 with a number of cellular partners involved in transcriptional regulation and chromatin remodeling. This suggests that γ-retroviruses have evolved the EBM to mimic a cognate interaction motif to achieve effective integration in host chromatin. Collectively, our findings identify key structural features of the ET domain of Brd4 that allow for interactions with both cellular and viral proteins.T he bromodomain and extraterminal domain (BET) family of proteins (Brd2, 3, 4, and T) play central roles in regulating cell fate (1). They have been implicated in diverse cellular phenomena, including inflammation, obesity, spermatogenesis, cancer, DNA damage repair, viral latency, and, more recently, γ-retroviral integration site selection (2-8). Most of these functions have been associated with its dual role as epigenetic reader and transcriptional activator (1-4).The BET family of proteins, as well as the extended BET family (Brd1,7,8,and 9), is characterized by two N-terminal bromodomains and the extraterminal (ET) domain, for which the proteins are named; Brd4 is known to occur in two different isoforms, with the longer variant containing a C-terminal motif (9) (Fig. 1A). The dual bromodomains recognize and bind acetylated lysines on histone H3 and H4 tails on chromatin (9-11), thereby tethering the protein and any associated factors to those histone posttranslational modifications (PTMs). Whereas recognition of select histone marks is achieved through the bromodomains, the overall high-affinity binding to chromatin is the result of cooperative binding to both its cognate PTMs and nonspecific binding to DNA wrapped around mononucleosomes through interaction with the conserved motifs A and B (12, 13). The C-terminal domain of the long Brd4 isoform functions in activation of RNA polymerase II via interactions with pTEFb (positive transcription elo...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction

Crowe

Larue

Yuan

et al. 2016

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

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“…Thus, BET proteins are a group of epigenetic regulators that bind to acetylated lysine on histone tails to regulate chromatin accessibility to transcription factors and RNA polymerase [7,8]. Numerous smallmolecule were developed to target BET proteins in pre-clinical models of cancers especially in hematological malignancies [9,10,12,[25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

“…Bromodomain and extra-terminal domain (BET) protein family (BRD2, BRD3, BRD4, and BRDT), through its ability to bind to acetylated lysine on histone tails, is an important class of "histone reading protein" [7]. Bromodomains act as a scaffold for molecular complexes at the recognized histone sites in order to regulate chromatin accessibility to transcription factors and RNA polymerase [8].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Baud’huin

Lamoureux

Jacques

et al. 2017

Bone

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Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.

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“…These inhibitors specifically target the KAc recognition sites of the BET family of proteins (BRD2, BRD3, BRD4, and BRDT), each containing two tandem BRDs (bromodomains BD1 and BD2) (11). BET bromodomain inhibitors exert a broad spectrum of desirable biological effects such as anticancer and anti-inflammatory properties (12).…”

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confidence: 99%

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

Pastori

Kapranov

Penas

et al. 2015

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

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Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumorpromoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.glioblastoma | long noncoding RNAs | epigenetics | BRD4 | I-BET151

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Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

Cited by 166 publications

References 85 publications

Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction

Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation

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