Toxoplasma gondii, an apicomplexan parasite, relies heavily on epigenetic regulation of gene expression, which is controlled by chromatin-modifying enzymes and histone acetylation, to invade and establish infection in the host. Bromodomain proteins are important epigenetic regulators in parasites, acting as 'readers' of histone lysine acetylation to control gene expression. While many bromodomain proteins are unique to parasites, only a few have been explored for therapeutic applications. In this study, we characterized the parasite-specific bromodomain protein TgBDP4 as a key epigenetic reader and a potential drug target for toxoplasmosis. Protein-peptide interaction and pull-down studies reveal that TgBDP4 interacts strongly with acetylated histone H3 as well as unphosphorylated and Ser5-phosphorylated forms of RNA polymerase II-CTD, which are necessary for gene activation. Using a conditional knockdown approach, we demonstrate that TgBDP4 is essential for parasite survival in both cell culture and a mouse host. When the therapeutic potential of TgBDP4 was evaluated using three bromodomain inhibitors, I-BRD9, (+)-JQ1, and I-BET151, we found that I-BRD9, a selective inhibitor of HsBRD9, effectively inhibits TgBDP4 activity at much lower concentrations than HsBRD9. This inhibition occurs through the binding of I-BRD9 to conserved key residues of the acetyl-lysine-binding pocket of TgBDP4, resulting in a complete arrest of parasite replication in culture and extending the survival time of infected mice. Overall, this study highlights the indispensable role of TgBDP4-mediated gene regulation for parasite survival, establishing TgBDP4 as a promising drug target for treating toxoplasmosis.

2025-06-01·ANTI-CANCER DRUGS

BRD9 promotes the malignant phenotype of thyroid cancer by activating the MAPK/ERK pathway

Article

作者: Yilin Li ; Hong Cao ; Yingcheng Deng

Thyroid cancer is one of the most common endocrine gland malignancies in China. During gene transcription, the bromodomain and extraterminal domain (BET) proteins perform epigenome interpretation tasks. Bromodomain-containing protein 9 (BRD9) is one of the BET family members. Increasing evidence has implicated that BRD9 plays significant roles in multiple malignancies. However, its role in thyroid cancer is still not fully understood. In this research, our results demonstrated that high expression of BRD9 can facilitate the malignant phenotype of thyroid cancer cell lines, while low expression of BRD9 can impede the malignant phenotype of thyroid cancer cell lines. Pharmacologically, I-BRD9 treatment inhibits the proliferation and promotes the rate of apoptosis in thyroid cancer cell lines. Moreover, our results also revealed that BRD9 promoted xenograft tumor growth. In addition, our study showed that the expression of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) pathway-related proteins was decreased in BRD9 knockdown thyroid cancer cells, such as Raf, ERK, p-ERK, c-Fos, and c-Myc, which could be significantly reversed by overexpressing the BRD9 in different thyroid cancer cells. After the specific inhibitor of ERK (SCH772984) was applied to thyroid cancer cells (BCPAP cells) overexpressing the BRD9 gene, the results suggested that SCH772984 reverses the high expression of MAPK/ERK pathway-associated protein in BCPAP cells (over-expression BRD9 cells). In conclusion, this study demonstrated that BRD9 was highly expressed in serum and malignant tumor tissues of thyroid cancer patients and further promoted the development of the malignant phenotype of thyroid cancer by activating the MAPK/ERK signaling pathway.

2025-03-31·FASEB JOURNAL

Exploring the impact of RPN1 on tumorigenesis and immune response in cancer

Article

作者: Zhimin Li ; Yongjun Jiang ; Yuanbin Tang ; Lijun Zeng ; Pengfei Luo ; Lunqi Luo ; Lianjie Ouyang ; Haodong He ; Yuehua Li ; Meiling Wen

Abstract:

The ribophorin family, including RPN1, has been associated with tumor progression, but its specific role in pan‐cancer dynamics remains unclear. Using data from TCGA, GTEx, and Ualcan databases, we investigated the relationship of RPN1 with prognosis, genomic alterations, and epigenetic modifications across various cancers. Differential analysis revealed elevated RPN1 expression in multiple cancer types, indicating a potential prognostic value. Amplification was the predominant mutation type of RPN1 in pan‐cancer, with notable correlations with DNA methylation and copy number variation. Gene set variation analysis identified RPN1's involvement in cancer development, immunity, and metabolism. Additionally, RPN1 expression correlated with the tumor microenvironment, immune response factors, and response to anti‐tumor therapies. Functional validation in triple‐negative breast cancer, glioblastoma, and bladder cancer cell lines demonstrated the role of RPN1 in tumor cell proliferation and migration. Our findings highlight RPN1 as a potential biomarker for cancer diagnosis and treatment response in pan‐cancer therapy.

项与 I-BRD9 相关的新闻（医药）

2023-12-05

·GlobeNewswire-Health Care

Rumi Scientific Announces Partnership with X-Chem for Development of Lead Candidate in Huntington’s Disease

NEW YORK, Dec. 05, 2023 (GLOBE NEWSWIRE) -- Rumi Scientific (“Rumi”), a developer of therapies for rare and neurodegenerative diseases using its high throughput organoid phenotypic screening platform, today announced that it has entered into a partnership with X-Chem, the leading provider of innovative solutions in early-stage drug discovery, through which X-Chem will develop a lead candidate BRD9 inhibitor for the treatment of Huntington’s Disease (HD). RUMI Scientific has identified bromodomain 9 (BRD9), an epigenetic reader, as a novel therapeutic target for HD with the potential to modify the disease's progression. The company has successfully validated this target in the R6/2 model of HD and in cellular models that replicate various aspects of the HD phenotype. A key result from these studies is that lowering of BRD9 levels can restore striatal volume a significant observation demonstrating disease modifying potential. “BRD9 inhibition is a novel target for the treatment of HD identified by our proprietary high throughput organoid phenotypic screening platform,” said Allen Fienberg, PhD, Chief Executive Officer of Rumi. “We have previously demonstrated, in vitro, that BRD9 inhibition rescues several of the biochemical dysfunctions known to occur in HD and thus could be disease modifying. We look forward to working closely with the team at X-Chem on the development of the lead molecule, and to advancing it toward clinical studies.” X-Chem is a leading drug discovery CRO with a proven track record in developing brain permeable compounds within the bromodomain class. Their expertise lies in leveraging state-of-the-art screening, advanced computational chemistry and machine learning, specialized synthesis, and process development to advance the most promising lead compounds, maintaining a focus on quality through multi-parameter optimization. Together, RUMI and X-Chem will meticulously design a screening cascade that maximizes speed, efficiency, predictive accuracy, and translational validity, harnessing RUMI's expertise in HD assays at the cellular and tissue levels. "We are excited to be partnering with RUMI Scientific in their pursuit of a lead candidate iBRD9 for HD” said Matt Clark, Ph.D., Chief Executive Officer of X-Chem. “RUMI Scientific's profound understanding of HD biology and their innovative drug discovery platform make them an ideal partner. We are particularly excited about the unique promise of the Rumi platform and its potential to discover additional novel targets that we can take to the next level." About Rumi ScientificRumi Scientific’s mission is to identify and develop novel therapeutics for rare and neurodegenerative diseases by employing its revolutionary synthetic human tissue platform to produce more predictive data leading to a safe and faster clinical trial process. The Company’s lead program is an orally available bromodomain-containing protein 9 (BRD9) inhibitor in lead optimization for the treatment of Huntington’s disease. Founded in 2016, Rumi licensed foundational technology from The Rockefeller University developed by co-founders Ali H. Brivanlou, Ph.D., and Eric D. Siggia, Ph.D. For more information on Rumi Scientific, please see www.rumiscientific.com or contact info@rumiscientific.com. Rumi Scientific:Allen Fienberg, Ph.D.Chairman and Chief Executive Officerallen@rumiscientific.com Fred Etoc, Ph.D.Chief Scientific Officerfred@rumiscientific.com Investors:Burns McClellan Lee Roth / Cameron Radinoviclroth@burnsmc.com / cradinovic@burnsmc.com

100 项与 I-BRD9 相关的药物交易

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