Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases

Padmanabhan, Balasundaram; Mathur, Shruti; Manjula, R; Tripathi, Shailesh

doi:10.1007/s12038-016-9600-6

Cited by 86 publications

(61 citation statements)

References 84 publications

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“…BRDs are protein modules that bind to e-N-acetylated lysine-containing sequences and modulate transcriptional processes. Members of the dual BRD-containing BET (bromo and extra terminal) proteins BRD2, BRD3, BRD4, and BRDT are targets of drugs currently pursued in oncology, neurological diseases, diabetes, atherosclerosis, and inflammation (35,36). To determine whether XMD8-92 and other ERK5 kinase inhibitors can likewise inhibit BRDs, we screened the compounds against BRD4, the most wellstudied and key member of the BET protein family.…”

Section: Resultsmentioning

confidence: 99%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

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

102

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Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.) is a member of the mitogen-activated protein kinase (MAPK) family, which includes ERK1/2, JNK1/2/3, and p38α/β/δ/γ (1). However, unlike the other MAPK members, ERK5 contains a unique 400-amino-acid C-terminal domain in addition to the kinase domain. Through the MAPK signaling cascade, mitogenactivated protein kinase kinase 5 (MEK5) activates ERK5 by phosphorylating the TEY motif in the N-terminal activation loop (2). This event unlocks the N-and C-terminal halves, allowing ERK5 to auto-phosphorylate multiple sites in its C-terminal region, which can then regulate nuclear shuttling and gene transcription (3, 4). Noncanonical pathways (including cyclin-dependent kinases during mitosis and ERK1/2 during growth factor stimulation) also exist for phosphorylation of sites in the ERK5 tail (5-7). Although ERK5 has been demonstrated to directly phosphorylate transcription factors (8-10), the noncatalytic C-terminal tail of ERK5 can also interact with transcription factors and influence gene expression (4,11,12).ERK5 can be activated in response to a range of mitogenic stimuli [e.g., growth factors, G protein-coupled receptor (GPCR) agonists, cytokines] and cellular stresses (e.g., hypoxia, shear stress) (13). Like most kinases including MAPK members, ERK5 function is assumed to be driven by its kinase activity. ERK5 deletion is embryonic lethal in mice and a variety of tissue-or development-stage restricted KOs have shown clear phenotypes, suggesting that the catalytic function and/or an aspect of the nonkinase domain(s) have key roles in development and mature organ function (14-18). The availability of the first ERK5 inhibitor ...

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Section: Resultsmentioning

confidence: 99%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

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

102

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“…Conditional PfBDP1 knockdown causes a significant defect in parasite invasion and growth (Josling et al, 2015). In parallel to these studies, several small molecule inhibitors have recently been reported to have a high affinity and specificity to bromodomains, and could represent a new therapeutic avenue in P. falciparum infection (Padmanabhan et al, 2016). …”

Section: Novel Parasite Factors Involved In Malarial Pathogenesis mentioning

confidence: 99%

Severe malaria: what’s new on the pathogenesis front?

Wassmer

Grau

2017

International Journal for Parasitology

106

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Plasmodium falciparum causes the most severe and fatal form of malaria in humans with over half a million deaths each year. Cerebral malaria (CM), a complex neurological syndrome of severe falciparum malaria, is often fatal and represents a major public health burden. Despite vigorous efforts, the pathophysiology of CM remains to be elucidated, thereby hindering the development of adjunctive therapies. In recent years, multidisciplinary and collaborative approaches have led to groundbreaking progress both in the laboratory and in the field. Here we review the latest breakthroughs in severe malaria pathogenesis, with a specific focus on new pathogenetic mechanisms leading to CM. The most recent findings point towards specific parasite phenotypes targeting brain microvasculature, endothelial dysfunction and subsequent oedema-induced brain swelling.

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“…One such modification is histone acetylation which relaxes chromatin structure by loosening their interaction with DNA, thereby facilitating gene expression. However, the functional role of acetylated histones is regulated by bromodomains and extra-terminal (BET) domain family proteins [5]. It has been reported that members of BET proteins such as Brd2, Brd3, Brd4 are associated with acetylated chromatin and facilitate transcriptional activation through increasing the effective molarity of recruited transcriptional activators [6]pharmacological inhibition of bromodomain proteins that bind acetylated chromatin marks may repress downstream gene expression.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological targeting of BET proteins inhibits renal fibroblast activation and alleviates renal fibrosis

et al. 2016

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Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively inhibit tumorgenesis and ameliorate pulmonary fibrosis by targeting bromodomain proteins that bind acetylated chromatin markers. However, their pharmacological effects in renal fibrosis remain unclear. In this study, we examined the effect of I-BET151, a selective and potent BET inhibitor, on renal fibroblast activation and renal fibrosis. In cultured renal interstitial fibroblasts, exposure of cells to I-BET151, or silencing of bromodoma in-containing protein 4 (Brd4), a key BET protein isoform, significantly reduced their activation as indicated by decreased expression of α-smooth muscle actin, collagen 1 and fibronectin. In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), administration of I-BET151 suppressed the deposition of extracellular matrix proteins, renal fibroblast activation and macrophage infiltration. Mechanistically, I-BET151 treatment abrogated UUO-induced phosphorylation of epidermal growth factor receptor and platelet growth factor receptor-β. It also inhibited the activation of Smad-3, STAT3 and NF-κB pathways, as well as the expression of c-Myc and P53 transcription factors in the kidney. Moreover, BET inhibition resulted in the reduction of renal epithelial cells arrested at the G2/M phase of cell cycle after UUO injury. Finally, injury to the kidney up-regulated Brd4, and I-BET151 treatment abrogated its expression. Brd4 was also highly expressed in human fibrotic kidneys. These data indicate that BET proteins are implicated in the regulation of signaling pathways and transcription factors associated with renal fibrogenesis, and suggest that pharmacological inhibition of BET proteins could be a potential treatment for renal fibrosis.

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Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases

Cited by 86 publications

References 84 publications

ERK5 kinase activity is dispensable for cellular immune response and proliferation

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Severe malaria: what’s new on the pathogenesis front?

Pharmacological targeting of BET proteins inhibits renal fibroblast activation and alleviates renal fibrosis

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