Article
Biochemistry & Molecular Biology
Amjad Ali, Jasmin Shafarin, Hema Unnikannan, Nour Al-Jabi, Rola Abu Jabal, Khuloud Bajbouj, Jibran Sualeh Muhammad, Mawieh Hamad
Summary: Combined inhibition of BRD4-RAC1 signaling pathways shows promising antitumor effects in different molecular subtypes of breast cancer, suppressing cell growth, migration, and stem cell expansion while inducing autophagy and cellular senescence. Co-targeting RAC1-BRD4 presents a novel therapeutic approach by disrupting key axis and epigenetic regulation in breast tumorigenesis.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Irene Marchesi, Milena Fais, Francesco Paolo Fiorentino, Valentina Bordoni, Luca Sanna, Stefano Zoroddu, Luigi Bagella
Summary: The effects of BET inhibitor JQ1 on the viability of RMS cells were evaluated in this study. It was found that the drug sensitivity of RMS cell lines to JQ1 was directly proportional to the expression of MYC. JQ1 induced G1 arrest in cells with high steady-state levels of MYC, and apoptosis was associated with MYC downregulation. These findings suggest that BET inhibition could be an effective strategy for the treatment of RMS.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Aubrey L. Miller, Patrick L. Garcia, Samuel C. Fehling, Tracy L. Gamblin, Rebecca B. Vance, Leona N. Council, Dongquan Chen, Eddy S. Yang, Robert C. A. M. van Waardenburg, Karina J. Yoon
Summary: Gemcitabine combined with a BET bromodomain inhibitor showed superior efficacy in treating pancreatic cancer compared to Gemcitabine alone, potentially by inhibiting DNA repair protein expression and enhancing DNA damage, as well as impacting proteins involved in cholesterol biosynthesis and lipid metabolism. The combination therapy also selectively inhibited the LXR/RXR activation pathway, suggesting a mechanism for its observed in vivo efficacy.
Article
Oncology
Patrick L. Garcia, Aubrey L. Miller, Ling Zeng, Robert C. A. M. van Waardenburg, Eddy S. Yang, Karina J. Yoon
Summary: This study shows that the combination of BET inhibitor JQ1 and ionizing radiation can increase DNA damage in pancreatic cancer cells by decreasing the levels of RAD51 protein, leading to a decrease in clonogenic potential. Furthermore, lower levels of BET proteins BRD2 or BRD4 increase sensitivity to JQ1 and JQ1 + IR.
FRONTIERS IN ONCOLOGY
(2022)
Article
Behavioral Sciences
C. J. Babigian, H. J. Wiedner, C. Wahlestedt, G. C. Sartor
Summary: Epigenetic mechanisms, specifically BET proteins, have been shown to play a significant role in psychostimulant-induced conditioned place preference (CPP) but not in opioid-induced CPP or contextual fear conditioning. Systemic administration of the BET inhibitor JQ1 resulted in a dose-dependent reduction in the acquisition of amphetamine and nicotine CPP in male mice.
BEHAVIOURAL BRAIN RESEARCH
(2022)
Article
Chemistry, Medicinal
Xuetao Chen, Fanying Meng, Jingtian Zhang, Zijian Zhang, Xuan Ye, Weikun Zhang, Yuanyuan Tong, Xinrui Ji, Rujun Xu, Xiao-Li Xu, Qi-Dong You, Zheng-Yu Jiang
Summary: Sepsis is a global health problem and BRD4 inhibitor 27 could be a potential candidate for sepsis treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Junhua Li, Run Zhu, Xiaoxi Zhuang, Cheng Zhang, Hui Shen, Xishan Wu, Maofeng Zhang, Cen Huang, Qiuping Xiang, Linxiang Zhao, Yong Xu, Yan Zhang
Summary: In this study, a class of novel BET bivalent inhibitors based on a monovalent BET inhibitor 7 (Y06037) was designed, optimized, and evaluated. The representative bivalent inhibitor 17b exhibited 32-fold greater potency in inhibiting cell growth in LNCaP compared to monovalent inhibitor 7. Furthermore, 17b induced 95.1% PSA regression in LNCaP cells at a concentration of 2 μM. Docking study revealed the potential binding mode of 17b with two BET bromodomains. These findings suggest that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.
BIOORGANIC CHEMISTRY
(2023)
Article
Oncology
Moein Ala
Summary: C-Myc overexpression in pancreatic cancer is associated with aggressive behavior of cancer cells and can regulate various cellular processes. Recent studies have shown that C-Myc can be targeted directly or indirectly, offering potential therapeutic strategies for pancreatic cancer.
CANCER BIOLOGY & THERAPY
(2022)
Article
Oncology
Ana P. Kutschat, Feda H. Hamdan, Xin Wang, Alexander Q. Wixom, Zeynab Najafova, Christine S. Gibhardt, Waltraut Kopp, Jochen Gaedcke, Philipp Strobel, Volker Ellenrieder, Ivan Bogeski, Elisabeth Hessmann, Steven A. Johnsen
Summary: Gemcitabine-resistant PDAC tumors show coamplification of RRM1 and STIM1, where RRM1 is required for resistance while high STIM1 levels lead to increased cytosolic calcium levels. This calcium influx impairs ER stress response and activates NFAT signaling, revealing a potential target for therapy in PDAC.
Article
Biology
Mami Tsume-Kajioka, Chiharu Kimura-Yoshida, Kyoko Mochida, Yoko Ueda, Isao Matsuo
Summary: BET proteins are essential for the specification and maintenance of the epiblast lineage during mouse preimplantation development, with BRD4 playing a central role and BRD2 acting complementarily.
Article
Biochemistry & Molecular Biology
Ziying Feng, Aiping Chen, Jing Shi, Daoguang Zhou, Wei Shi, Qianqian Qiu, Xinhong Liu, Wenlong Huang, Jieming Li, Hai Qian, Wenjie Zhang
Summary: Compound 58 has been identified as a novel BRD4 inhibitor with potent inhibitory effects on leukemia cell proliferation, potentially mediated through the down-regulation of the oncogene c-myc. In vivo pharmacokinetics studies showed favorable PK features compared to (+)-JQ1, indicating its potential for further development as a leukemia inhibitor.
BIOORGANIC CHEMISTRY
(2021)
Article
Oncology
Thomas K. Sears, Kevin D. Woolard
Summary: This study revealed that high expression of BRD4 is associated with decreased survival in glioma patients carrying IDHmut. Gliomas with IDHmut show increased sensitivity to the BET inhibitor JQ1, especially in terms of delayed cytotoxicity. Epigenetic-targeting drugs may serve as effective therapeutic strategies for IDHmut gliomas.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Cong Wang, Huasong Lu, Xiangzhong Liu, Xiang Gao, Wenjing Tian, Haifeng Chen, Yuhua Xue, Qiang Zhou
Summary: The BET-bromodomain protein BRD4 utilizes two bromodomains to target acetyl-histones and other domains, stimulating transcription of proto-oncogenes and key cell identity genes. Recent studies highlight the importance of BRD4's ability to form phase-separated condensates that cluster at the super-enhancer regions of target genes. Through the discovery of a natural product called PCG, derived from the Chinese medicinal herb polygonum cuspidatum Sieb. et Zucc., a BET inhibitor that selectively targets BRD4 and suppresses phase separation, a unique mechanism of action among known BET inhibitors, has been identified.
Article
Pharmacology & Pharmacy
Thibaut Fourniols, Valentina Maggio, Diana Rafael, Ariana Colaco, Elia Garcia Vidal, Alessandra Lopes, Simo Schwartz, Agueda Martinez-Barriocanal, Veronique Preat, Diego Arango
Summary: In this study, we evaluated the therapeutic effect of two new nano-formulations of BETi JQ1 for the treatment of colorectal cancer. The results showed that although nanoencapsulation improved the delivery of JQ1 to tumors, it did not enhance its anticancer effect. Additionally, MYC inhibition did not affect the efficacy of JQ1 in the CT26 CRC mouse model.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2022)
Article
Chemistry, Medicinal
Gerald Thiel, Oliver G. Roessler
Summary: TRPM3 calcium channels regulate various biological functions, including gene transcription. Stimulation of TRPM3 channels activates stimulus-responsive transcription factors, which bind to short cognate sequences in the promoters of their target genes. Transcriptional coactivators and acetyl-lysine-bound bromodomain proteins are required for TRPM3-induced signaling to activate gene transcription.