Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

Yin, Mingzhu; Guo, Ying; Hu, Rui; Cai, Wesley L.; Li, Yao; Pei, Shiyao; Sun, Huan; Peng, Cong; Li, Jiali; Ye, Rui; Yang, Qinghua; Wang, Nenghui; Tao, Yongguang; Yan, Qin

doi:10.1038/s41467-020-15290-0

Cited by 122 publications

(120 citation statements)

References 57 publications

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“…The abnormal activity of the BET protein, which recognizes lysine residues of both histones and non-histones, especially BRD4, is closely associated with cancer progression, making BET a promising therapeutic target [ 313 , 314 ]. The BET small molecule inhibitors can be used as a promising alternative cancer therapy [ 315 ]. Thus, BET inhibitors such as ABBV-075, ABBV-744, BAY 1238097, BMS-986158, CPI-0610, FT-1101, GS-5829, GSK-2820151, GSK-525762, BI-894999, RO-6870810 and OTX-015, have been used to study their efficacy as cancer therapies in clinical trials [ 312 ].…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

“…Thus, BET inhibitors such as ABBV-075, ABBV-744, BAY 1238097, BMS-986158, CPI-0610, FT-1101, GS-5829, GSK-2820151, GSK-525762, BI-894999, RO-6870810 and OTX-015, have been used to study their efficacy as cancer therapies in clinical trials [ 312 ]. Among them, BMS-986158, OTX-015 and GSK-525762 inhibitors are three major clinical stage BET inhibitors [ 315 ].…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

“…Although hypoxia increased the recruitment of BRD4 to CA9 and VEGF-A in tumor cells, the down-regulated CA9 and VEGF-A in tumor cells treated with JQ1 indicated that JQ1 affected the hypoxia response in which BRD4 participated [ 318 ]. Recently, Chen and Yin et al found that NHWD-870, a novel BRD4 inhibitor, effectively inhibited the expression of BRD4 and its target gene HIF-1α [ 315 ]. NHWD-870 significantly inhibits tumor growth in a variety of animal tumor models [ 315 ].…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

“…Recently, Chen and Yin et al found that NHWD-870, a novel BRD4 inhibitor, effectively inhibited the expression of BRD4 and its target gene HIF-1α [ 315 ]. NHWD-870 significantly inhibits tumor growth in a variety of animal tumor models [ 315 ]. Mechanistically, NHWD-870 reduces the expression and secretion of macrophage colony stimulating factor 1 (CSF1) in tumor cells by blocking the functional activity of BRD4 and its target gene HIF-1α [ 315 ].…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

“…NHWD-870 significantly inhibits tumor growth in a variety of animal tumor models [ 315 ]. Mechanistically, NHWD-870 reduces the expression and secretion of macrophage colony stimulating factor 1 (CSF1) in tumor cells by blocking the functional activity of BRD4 and its target gene HIF-1α [ 315 ]. Down-regulation of CSF1 weakens the activation degree of ERK1/2 and PI3K/AKT pathways, leading to decreased proliferation and survival of tumor associated macrophages (TAMs) [ 315 ].…”

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

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Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

Section: Hypoxia and Targeted Therapy Via Epigenetic Interferencementioning

confidence: 99%

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Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

et al. 2022

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Recent evidence has indicated that overexpression of the epigenetic reader bromodomain‐containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano‐PROTAC (CREATE (CRV‐LLC membrane/DS‐PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)‐responsive polymer (disulfide bond‐linked poly(lactic‐co‐glycolic acid), DS‐PLGA) to load BRD4‐targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor‐associated macrophages (TAMs). The pH/GSH‐responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor‐bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano‐PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC.

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Stimuli‐Responsive PROTACs for Controlled Protein Degradation

Deng

Chi

et al. 2023

Angewandte Chemie

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Proteolysis Targeting Chimeras (PROTACs) represent a promising therapeutic modality to address undruggable and resistant issues in drug discovery. However, potential on‐target toxicity remains clinically challenging. We developed a generalized caging strategy to synthesize a series of stimuli‐responsive PROTACs (sr‐PROTACs) with diverse molecular blocks bearing robust and cleavable linkers, presenting “turn on” features in manipulating protein degradation. By leveraging pathological cues, such as elevated ROS, phosphatase, H2S, or hypoxia, and external triggers, such as ultraviolet light, X‐Ray, or bioorthogonal reagents, we achieved site‐specific activation and traceless release of original PROTACs through de‐caging and subsequent self‐immolative cleavage, realizing selective uptake and controlled protein degradation in vitro. Especially, in vivo study revealed that two sr‐PROTACs with phosphate‐ and fluorine‐containing cages exhibited high solubility and long plasma exposure, and were specifically activated by tumor overexpressing phosphatase or low dosage of X‐Ray irradiation in situ, leading to efficient protein degradation and potent tumor remission. With more reactive biomarkers to be screened from clinical practice, our caging library could provide a general tool to design activatable PROTACs, prodrugs, antibody drug conjugates, and smart biomaterials for personalized treatment, tissue engineering or regenerative medicine.

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Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

Cited by 122 publications

References 57 publications

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

Stimuli‐Responsive PROTACs for Controlled Protein Degradation

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