Insight into selective mechanism of class of I‐BRD9 inhibitors toward BRD9 based on molecular dynamics simulations

Su, Jing; Liu, Xinguo; Zhang, Shaolong; Yan, Fangfang; Chen, Jianzhong

doi:10.1111/cbdd.13398

Cited by 34 publications

(25 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, small-molecule inhibitors of the BRD9 bromodomain selectively suppress tumor cell proliferation and survival and induce apoptosis. 27,75,102,103 Indeed, scientists have researched and developed several effective BRD9 bromodomain inhibitors, such as BRD9 selective inhibitors (I-BRD9, 104 BI-7273, 105 and BI-9564 106 ) and BRD7/9 inhibitors. 107,108 LP99 is the first reported selective BRD7/9 inhibitor that effectively inhibits the binding of BRD7/9 to acetylated histones in vivo and in vitro; Moreover, LP99 inhibits the secretion of proinflammatory cytokine IL-6.…”

Section: Cancer Therapeutics For Targeting Brd9mentioning

confidence: 99%

“…117 Studies on the selection mechanism of I-BRD9 for the BRD9 bromodomain have demonstrated that several residues in the ZA and ZB loops of the bromodomain, such as Asp144, Ile53, Lys91, Thr104, Pro82, Asn140, Asn100, and Phe44, can be used as important references for designing BRD9 inhibitors. 104 The imidazo [1,5-a] pyrazin-8 (7H) -one derivative was designed and synthesized using the interaction of the inhibitor with the Asn and Tyr residues to inhibit BRD9 activity. 118 In addition to the synthesis and design of protein inhibitors, targeting protein degradation by hijacking the ubiquitinproteasome system can be another therapeutic strategy.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Targeting BRD9 for Cancer Treatment: A New Strategy

Zhu¹,

Liao²,

Tang³

2020

OTT

View full text Add to dashboard Cite

Bromodomain-containing protein 9 (BRD9) is a newly identified subunit of the non-canonical barrier-to-autointegration factor (ncBAF) complex and a member of the bromodomain family IV. Studies have confirmed that BRD9 plays an oncogenic role in multiple cancer types, by regulating tumor cell growth. The tumor biological functions of BRD9 are mainly due to epigenetic modification mediated by its bromodomain. The bromodomain recruits the ncBAF complex to the promoter to regulate gene transcription. This review summarizes the potential mechanisms of action of BRD9 in carcinogenesis and the emerging strategies for targeting BRD9 for cancer therapeutics. Although the therapeutic potential of BRD9 has been exploited to some extent, research on the detailed biological mechanisms of BRD9 is still in its infancy. Therefore, targeting BRD9 to study its biological roles will be an attractive tool for cancer diagnosis and treatment, but it remains a great challenge.

show abstract

Section: Cancer Therapeutics For Targeting Brd9mentioning

confidence: 99%

mentioning

confidence: 99%

Targeting BRD9 for Cancer Treatment: A New Strategy

Zhu¹,

Liao²,

Tang³

2020

OTT

View full text Add to dashboard Cite

show abstract

“…Finally, we did not explore the mechanism of BRD-containing protein genes in HCC and evaluate the potential therapeutic effects between BRDs and anticancer drugs. Recent studies have focused on the selective mechanism of inhibitors toward BRD-containing protein genes such as BRD4 and BRD9 based on molecular dynamics simulations [ 56 , 57 ]. Further researches are needed to explore the exact mechanism and therapeutic roles of BRDs in HCC.…”

Section: Discussionmentioning

confidence: 99%

BRD4/8/9 are prognostic biomarkers and associated with immune infiltrates in hepatocellular carcinoma

Chen

Ouyang

Chen

et al. 2020

Aging

View full text Add to dashboard Cite

Bromodomain (BRD)-containing proteins are a class of epigenetic readers with unique recognition for N-acetyl-lysine in histones and functions of gene transcription and chromatin modification, known to be critical in various cancers. However, little is known about the roles of distinct BRD-containing protein genes in hepatocellular carcinoma (HCC). Most recently, we investigated the transcriptional and survival data of BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9 in HCC patients through ONCOMINE, UALCAN, Human Protein Atlas, GEPIA, cBioPortal, STRING, TIMER databases. BRD1/2/3/4/7/8/9 were over-expressed in HCC and were significantly associated with clinical cancer stages and pathological tumor grades. High mRNA expressions of BRD4/8/9 were promising candidate biomarkers in HCC patients. The rate of sequence alternations in BRD1/2/3/4/7/8/9 was relatively high (52%) in HCC patients, and the genetic alternations were correlated with shorter overall survival and disease-free survival in HCC patients. Additionally, the mRNA expression levels of individual BRD genes were significantly positively associated with the immune infiltrating levels of B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells. And the associations between BRD1/2/3/4/7/8/9 and diverse immune marker sets showed a significance. Overall, these results indicated that BRD4/8/9 could be potential prognostic markers and druggable epigenetic targets in HCC patients.

show abstract

“…The depletion of the BRD9 subunit of the BAF and ncBAF complexes leads to cell death in both SS and MRT (122, 123). This is particularly interesting given the recent development of potent and specific BRD9 targeting compounds (124–128). Another synthetic lethal target for SS is the DNA damage response kinase ATR, which has been shown to impair growth of patient-derived SS xenografts (129).…”

Section: Novel Epigenetic Therapeutic Approachesmentioning

confidence: 99%

Epigenetic Targets in Synovial Sarcoma: A Mini-Review

et al. 2019

View full text Add to dashboard Cite

Synovial Sarcomas (SS) are a type of Soft Tissue Sarcoma (STS) and represent 8–10% of all STS cases. Although SS can arise at any age, it typically affects younger individuals aged 15–35 and is therefore part of both pediatric and adult clinical practices. SS occurs primarily in the limbs, often near joints, but can present anywhere. It is characterized by the recurrent pathognomonic chromosomal translocation t(X;18)(p11.2;q11.2) that most frequently fuses SSX1 or SSX2 genes with SS18. This leads to the expression of the SS18-SSX fusion protein, which causes disturbances in several interacting multiprotein complexes such as the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, also known as the BAF complex and the Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). Furthermore, this promotes widespread epigenetic rewiring, leading to aberrant gene expression that drives the pathogenesis of SS. Good prognoses are characterized predominantly by small tumor size and young patient age. Whereas, high tumor grade and an increased genomic complexity of the tumor constitute poor prognostic factors. The current therapeutic strategy relies on chemotherapy and radiotherapy, the latter of which can lead to chronic side effects for pediatric patients. We will focus on the known roles of SWI/SNF, PRC1, and PRC2 as the main effectors of the SS18-SSX-mediated genome modifications and we present existing biological rationale for potential therapeutic targets and treatment strategies.

show abstract

Insight into selective mechanism of class of I‐BRD9 inhibitors toward BRD9 based on molecular dynamics simulations

Cited by 34 publications

References 70 publications

Targeting BRD9 for Cancer Treatment: A New Strategy

Targeting BRD9 for Cancer Treatment: A New Strategy

BRD4/8/9 are prognostic biomarkers and associated with immune infiltrates in hepatocellular carcinoma

Epigenetic Targets in Synovial Sarcoma: A Mini-Review

Contact Info

Product

Resources

About