BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
·
IF 3.5
Xinye Chen,Cheng Wang,Dehua Lu,Heng Luo,Shang Li,Fucheng Yin,Zhongwen Luo,Ningjie Cui,Lingyi Kong,Xiaobing Wang
Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28 , encoded as KWCX-28 , was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC 50 = 1.86 µM), induced HCT-116 cells apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INFLAMMATION RESEARCH
·
2026
·Vol. 75
·期 1
·79
·
IF 6.2
Zhao Junyong,Luo Xiaolin,Wang Zelan,Luo Wenjian,Wu Shaofa,Ma Xingyu,Liu He,Chen Yang,Pi Shixian,Zhang Jiawen,Zhang Jihang,Liu Chuan,Bi Xianjin,Qin Zhexue
Aims Vascular calcification (VC) predicts cardiovascular risk in diabetes, chronic kidney disease (CKD) and atherosclerosis patients and is closely linked to the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Our previous work revealed that cGAS-STING signalling pathway in VSMCs increases CKD-associated atherosclerotic plaque vulnerability and recent studies elucidated the involvement of STING in vascular calcification, but its upstream modulation mechanism remains to be elucidated. Methods and results DNA damage and robust upregulation of STING occurred in high phosphate (Pi)-stimulated VSMCs, calcified aortic tissues from 1,25(OH) 2 VitD 3 (VitD 3 )-overloaded mice and radial arteries from CKD patients, and these changes were accompanied by the activation of the cGAS‒STING signalling pathway. STING deficiency alleviated vascular calcification in CKD model mice. STING knockdown suppressed calcium deposition and the expression of osteogenic transdifferentiation markers in VSMCs, whereas the overexpression of STING or its agonist 2′,3′-cGAMP exacerbated VC. Mechanistically, Brd4 was identified as a critical epigenetic regulator of Pi-induced DNA damage, STING activation and VC. Furthermore, the N6-methyladenosine (m6A) modification of STING mRNA was significantly increased in Pi-stimulated VSMCs, increasing its stability. Brd4 depletion decreased the m6A modification of STING and accelerated its degradation. The m6A modification of STING was mediated by the core methyltransferase Mettl3, whose transcription was regulated by Brd4. Finally, C-176 showed translational potential by effectively suppressing vascular calcification and osteogenesis markers expression in both VitD 3 -overloaded mice and Pi-stimulated VSMCs. Conclusions Our study elucidated the interplay between Brd4-mediated epigenetic and Mettl3-dependent epitranscriptomic mechanisms governs STING m6A modification and STING may be a potential therapeutic target for vascular calcification.
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2020
·Vol. 7
·期 7
·1902926
·
IF 15.84
Chen-Song Huang,Xinru You,Chunlei Dai,Qiong-Cong Xu,Fuxi Li,Li Wang,Xi-Tai Huang,Jie-Qin Wang,Shi-Jin Li,Zhuoxing Gao,Jun Wu,Xiao-Yu Yin,Wei Zhao
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant cancer with complex genomic variations, and no targetable genomic lesions have been found yet. Super-enhancers (SEs) have been found to contribute to the continuous and robust oncogenic transcription. Here, histone H3 lysine 27 acetylation (H3K27ac) is profiled in PDAC cell lines to establish SE landscapes. Concurrently, it is also shown that PDAC is vulnerable to the perturbation of the SE complex using bromodomain-containing protein 4 (BRD4) inhibitor, JQ1, synergized with cyclin-dependent kinase 7 (CDK7) inhibitor, THZ1. Formulations of hydrophobic l-phenylalanine-poly (ester amide) nanoparticles (NPs) with high drug loading of JQ1 and THZ1 (J/T@8P4s) are further designed and developed. J/T@8P4s is assessed for size, encapsulation efficiency, morphology, drug release profiles, and drug uptake in vitro. Compared to conventional free drug formulation, the nanodelivery system dramatically reduces the hepatotoxicity while significantly enhancing the tumor inhibition effects and the bioavailability of incorporated JQ1 and THZ1 at equal doses in a Gemcitabine-resistant PDAC patient-derived xenograft (PDX) model. Overall, the present study demonstrates that the J/T@8P4s can be a promising therapeutic treatment against the PDAC via suppression of SE-associated oncogenic transcription, and provides a strategy utilizing NPs to assist the drug delivery targeting SEs.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
癌症生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-16
·
IF 9.6
Yang Mengxue,Wang Ting,Shao Jingrong,Ran Xinna,Xiao Rui,Zhao Rui,Wu Chunyan,Ji Ming,Tian Weiping,Sun Huabing,Liu Jiao,Zuo Shengkai
Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.
研究领域:
心脏病学
·
分子生物学
·
药理学
·
细胞死亡
·
表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2026
·
IF 14.6
Xiaolan Xu,Chenxia Bai,Jiqiang Qu,Yinghou Wang,Qing Yan,Xiaohua Ran,Jiaming Zhang,Yangyang Liu,Jing Li,Lianghui Peng,Zhihui Sun,Guozheng Liu,Tianhong Zhang,Zhonggui He,Jin Sun,Jingyi Zhang,Jingdong Xiao,Qikun Jiang
The therapeutic potential of DNA-damaging agents like the topoisomerase I inhibitor exatecan (Exa) is frequently hindered by two major limitations: unfavorable physicochemical properties and intrinsic cellular defense mechanisms such as DNA repair pathways. To address these challenges, four albumin-binding prodrugs (C8-Exa, C12-Exa, C14-Exa, and C16-Exa) were developed by conjugating Exa with saturated fatty acids of varying chain lengths as albumin-binding motifs, integrated with a valine-citrulline dipeptide linker for cathepsin B (CTSB)-responsive activation, enabling their formulation into albumin nanoparticles (ANPs). Structure–activity relationship studies revealed a pseudo-parabolic trend in both albumin affinity and CTSB responsiveness as a function of fatty-acid chains, with C14-Exa ANPs achieving the optimal balance. C14-Exa ANPs exhibited superior albumin affinity, drug release kinetics, colloidal stability, and pharmacokinetics, achieving stronger tumor regression. To further amplify DNA-damaging therapeutics, hybrid ANPs (C14-ARV ANPs) were engineered by co-assembling C14-Exa with the BRD4-targeting PROTAC ARV-825, which acts through an “empty extinguisher” mechanism to disable DNA repair defenses. This dual-functional nanoplatform synergistically suppresses tumor growth by combining a structure-optimized Exa prodrug that ensures efficient DNA damage induction with ARV-825-mediated BRD4 degradation, which disrupts DNA damage repair progression and promotes apoptosis. This work establishes a rational nanoplatform design to enhance DNA damage-amplified cancer therapy.
✓ 已验证
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Weihe Zhao,Xiangdong Xu,Shu An,Juehui Wu,Haiyang Wang,Jinmei Luo,Youyuan Yuan,Laisheng Li
Radiotherapy (RT) is a key component of comprehensive cancer treatment regimens; nevertheless, its concomitant immunosuppression may diminish therapeutic efficacy. In this study, we developed an injectable hydrogel system for the local delivery of PROteolysis TArgeting Chimeras (PROTACs), achieved by loading tumor cell membrane-fused liposome nanoparticles to enhance the anti-tumor effect. The system targeted Bromodomain-containing protein 4 (BRD4), and combined treatment with RT promoted DNA damage, reduced DNA repair and decreased tumor cell proliferation and survival. Additionally, this strategy effectively promoted dendritic cell (DC) maturation, enhanced tumor-specific T cell infiltration, reversed radiotherapy-induced immunosuppression and boosted the anti-tumor immune response. This strategy expands the application of PROTAC technology in counteracting radiotherapy-induced immunosuppression and provides an important basis for subsequent biomedical translation and clinical development.
研究领域:
肿瘤学
·
生物化学
·
免疫学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Zhengquan Zhu,Yihan Wang,Haiyun Chen,Xinye Yu,Tingyu Wang,Yajing Weng,Meihong Guo,Ying Huang,Gaojian Tao,Wangsen Cao,Yong Wang,Daojuan Wang
Persistent androgen receptor (AR) activation is an important contributor to polycystic ovary syndrome (PCOS) and is affected by transcriptional regulation via histone acetylation; however, the underlying mechanisms are partially understood. This study demonstrated that AR activation in ovarian granulosa cells (GCs) of both dehydroepiandrosterone (DHEA) and high-fat diet-induced PCOS mouse models correlated with a significant increase in the histone acetyltransferase p300 and histone acetylation. Conversely, GC-specific p300 knockout or pharmacological inhibition with C646/A-485 effectively reduced AR activation, histone 3 acetylation (H3K18ac/H3K27ac), and ovarian fibrosis in PCOS mice, highlighting p300 as a critical driver. ATAC-seq and RNA-seq identified “open” chromatin regions at the AR promoter in PCOS ovaries, corresponding with increased AR transcription and histone acetylation. p300, along with transcription factor SP1 and the acetyl-reader BRD4, bound to H3K18ac and H3K27ac of the AR promoter in PCOS-modeled ovaries and GCs, which was blocked by C646 and the SP1 inhibitor Plicamycin, respectively. Importantly, continuous AR activation by its ligand DHT largely diminished the anti-fibrotic and ovarian-protective effects of C646. These findings suggest that p300, SP1, and BRD4, form a critical transcriptional complex driving AR activation and PCOS development, and that targeting the p300/AR axis may present a promising therapeutic approach for treating PCOS.
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Mengqing Gao,Minhui Shi,Hao Ding,Lei Xu,Na Zhao,Li Wang,Shujuan Huang,Hui Jiang,Ekaterina Bourova-Flin,Jianqing Mi,Saadi Khochbin,Domenico Iuso,Xiaoyu Zhu
Mitochondria-driven histone lysine succinylation is emerging as a critical signaling system that links cellular metabolism to the pathogenesis of diseases, including cancer. Here, we report that a global increase in protein/histone succinylation is associated with mitochondrial tricarboxylic acid cycle defects in acute myeloid leukemia (AML). Depletion of the succinyl-coenzyme A (CoA) synthetase alpha subunit SUCLG1 causes protein/histone hypersuccinylation in leukemia cells, which impairs cell proliferation and leukemia progression in xenograft models. Mechanistically, increased histone succinylation, which could compete with acetylation, attenuates the interaction of the bromodomain-containing protein 4 (BRD4) bromodomain with chromatin, hence disrupting BRD4-mediated leukemogenic gene transcription and restoring BRD4-dependent fine-tuned gene regulatory circuits. Our study uncovers the crucial role of metabolism-controlled histone succinylation in cancer development and highlights it as an innovative therapeutic approach.
研究领域:
癌症生物学
·
表观遗传学
·
细胞生物学
·
分子生物学
·
白血病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Chunhui Shan,Qi Bing,Gang Qiu,Hui Zhang,Yingmin Chen
Galectin-3 disrupts microglial P2X7R/MerTK balance after stroke • ERK/ROS/BRD4 axis mediates Gal-3-induced P2X7R upregulation • Gal-3 promotes cGAS-STING inflammation and apoptosis via HIF1α/P2X7R • TD-139 restores P2X7R/MerTK balance and reduces cerebral infarction • Targeting Gal-3 improves motor, cognitive, and grip strength in MCAO rats This study demonstrates that Galectin-3 (Gal3) exacerbates cerebral infarction progression by modulating the P2X7R/MerTK equilibrium in microglia via the ERK/BRD4/HIF1α signaling axis, with reactive oxygen species (ROS) serving as a potential intermediate mediator linking ERK activation to BRD4 upregulation based on prior literature evidence. Single-cell transcriptomic analysis revealed that ischemia drives microglia from a homeostatic state to an activated disease phenotype, and virtual Gal3 knockout predicted corresponding downregulation of BRD4. Using a rat model of cerebral infarction, we found that the Gal3 inhibitor TD-139 significantly reduced infarct volume, promoted M2 polarization of microglia, and improved neurological function in behavioral assays. Mechanistic investigations in BV2 microglia revealed that Gal3 activates ERK1/2, leading to ROS accumulation, BRD4 upregulation, and subsequent HIF1α-mediated P2X7R transcription, while suppressing KLF4 and MerTK. This cascade increased P2X7R expression and suppressed MerTK/KLF4 expression, generating a pro-inflammatory and pro-apoptotic microenvironment. Notably, pharmacological inhibition of Gal3 enhanced efferocytosis and reduced apoptosis, whereas P2X7R blockade exerted similar neuroprotective effects. These findings identify Gal3 as a key regulator of microglial polarization via the experimentally validated ERK/BRD4/HIF1α-P2X7R signaling cascade, where P2X7R activation concurrently triggers cGAS-STING-mediated pro-inflammatory/pyroptotic responses and suppresses the KLF4/MerTK efferocytosis axis. Targeting this regulatory network could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Targeting this pathway could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Data were analysed using one-way ANOVA followed by Tukey's post-hoc test for multiple comparisons; P < 0.05 was considered statistically significant.
✓ 已验证
DOI
高影响因子
Cell Reports
·
2023
·Vol. 42
·期 9
·113090-113090
·
IF 8.8
Wang D,Zhu Z,Fu Y,Zhang Q,Zhang Y,Wang T,Weng Y,Wen Y,Cao W,Tao G,Wang Y
Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcription is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone- and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation "reader" BRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1α. BRD4 and HIF-1α inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhibitor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.
研究领域:
内分泌学
·
生殖医学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Haiyang Wang,Yixuan Hou,Taian Lin,Ihsan Ullah,Qing Xu,Ye Liu,Taosha Jin,Yangning Zhang,Youyong Yuan
Radiotherapy (RT) is commonly employed to prevent postoperative recurrence, typically delivered in fractionated doses to mitigate side effects. However, multi-course RT frequently leads to radiation resistance and immunosuppression. In this study, a sono-responsive hydrogel that enables fractionated releases of PROteolysis TArgeting Chimeras (PROTAC) in response to ultrasound (US) pulses is presented. This system targets bromodomain-containing protein 4 (BRD4) and releases the PROTAC at the tumor site before each course of RT. This release inhibits DNA repair mechanisms and reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), thereby mitigating RT resistance and immune suppression. This strategy significantly improves the therapeutic efficacy of postoperative RT, reducing the risk of tumor recurrence. Overall, this work proposes an easy-to-implement strategy for overcoming challenges in resistance and immunosuppression in multi-course postoperative RT.
研究领域:
生物医学工程
·
肿瘤学
·
药学
·
免疫学
·
放射生物学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2019
·Vol. 38
·期 1
·1-12
·
IF 5.646
Shi Weidong,Zhang Chenyue,Ning Zhouyu,Hua Yongqiang,Li Ye,Chen Lianyu,Liu Luming,Chen Zhen,Meng Zhiqiang
Background Long non-coding RNA LINC00346 has been recently suggested as a prognostic marker in pancreatic cancer. However, its biological function in pancreatic cancer has not yet been determined. In this study, we attempted to ascertain the role of LINC00346 in regulating the aggressiveness of pancreatic cancer.Methods The effects of overexpression and knockdown of LINC00346 on the proliferation, cell cycle progression, apoptosis, and gemcitabine resistance were investigated. Bioinformatic analysis, luciferase reporter assay, and RNA immunoprecipitation assay were performed to search for potential microRNAs (miRs) that can interact with LINC00346.Results Overexpression of LINC00346 significantly enhanced the proliferation, colony formation, and tumorigenesis of pancreatic cancer cells. Conversely, knockdown of LINC00346 suppressed pancreatic cancer cell proliferation and caused a cell-cycle arrest at the G2/M-phase. Depletion of LINC00346 also enhanced gemcitabine sensitivity in pancreatic cancer cells both in vitro and in vivo. Mechanistic investigation revealed that LINC00346 acted as a sponge for miR-188-3p and blocked the repression of BRD4 by miR-188-3p in pancreatic cancer cells. Clinical evidence indicated a negative correlation between LINC00346 and miR-188-3p in pancreatic cancer specimens. Rescue experiments showed that LINC00346 attenuated the growth-suppressing and chemosensitizing effects of miR-188-3p on pancreatic cancer cells. In addition, silencing of BRD4 significantly inhibited LINC00346-induced pancreatic cancer cell proliferation and colony formation.Conclusion sLINC00346 shows the ability to promote pancreatic cancer growth and gemcitabine resistance, which is in part mediated by antagonization of miR-188-3p and induction of BRD4. Targeting LINC00346 may improve gemcitabine-based therapeutic efficacy.
研究领域:
肿瘤学
·
分子生物学
·
癌症遗传学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）