Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Artículo científico |
| Language: | en |
| Published: |
European journal of medicinal chemistry
2026
|
| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41544579/ |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1868266097720950784 |
|---|---|
| author | Fang, Zhangyun Zhan, Shuai Mao, Churu Zhang, Ningjing Zhao, Xiaofeng Huang, Yun Ding, Wanjing Ma, Zhongjun |
| author_facet | Fang, Zhangyun Zhan, Shuai Mao, Churu Zhang, Ningjing Zhao, Xiaofeng Huang, Yun Ding, Wanjing Ma, Zhongjun Fang, Zhangyun Zhan, Shuai Mao, Churu Zhang, Ningjing Zhao, Xiaofeng Huang, Yun Ding, Wanjing Ma, Zhongjun |
| collection | PubMed - marine biology |
| contents | Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer. Fang, Zhangyun Zhan, Shuai Mao, Churu Zhang, Ningjing Zhao, Xiaofeng Huang, Yun Ding, Wanjing Ma, Zhongjun Bromodomain Containing Proteins Humans Animals Cell Cycle Proteins Antineoplastic Agents Colorectal Neoplasms Transcription Factors Mice Administration, Oral Cell Proliferation Structure-Activity Relationship Drug Discovery Pyridones Drug Screening Assays, Antitumor Dose-Response Relationship, Drug Molecular Structure Biological Availability Mice, Nude Neoplasms, Experimental Colorectal cancer (CRC) remains a major clinical burden with limited durable responses. Given reports implicating Bromodomain-containing protein 4 (BRD4) in CRC proliferation and therapy resistance, more potent BRD4-targeting agents with proven in-vivo activity are needed. Through virtual screening followed by structure-guided chemical modification, we identified H5 as a BRD4 inhibitor. In biochemical assays, H5 shows IC = 7.9 ± 0.5 nM, outperforming JQ-1 (IC = 33.0 ± 1.0 nM) by 4-fold. Molecular dynamics simulations indicate that H5 engages BRD4 via hydrogen bonds with Asn140 and Asp88 and a water-mediated bridge to Gln85. In the HCT-116 xenograft mouse model, oral administration of H5 suppressed tumor growth (TGI = 82 % at 50 mg/kg) and downregulated the BRD4-driven oncoproteins c-MYC and BCL-2. Collectively, H5 emerges as a highly promising BRD4-targeted candidate for colorectal cancer treatment. |
| format | Artículo científico |
| id | pubmed_41544579 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | European journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer. Fang, Zhangyun Zhan, Shuai Mao, Churu Zhang, Ningjing Zhao, Xiaofeng Huang, Yun Ding, Wanjing Ma, Zhongjun Bromodomain Containing Proteins Humans Animals Cell Cycle Proteins Antineoplastic Agents Colorectal Neoplasms Transcription Factors Mice Administration, Oral Cell Proliferation Structure-Activity Relationship Drug Discovery Pyridones Drug Screening Assays, Antitumor Dose-Response Relationship, Drug Molecular Structure Biological Availability Mice, Nude Neoplasms, Experimental Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer. Fang, Zhangyun Zhan, Shuai Mao, Churu Zhang, Ningjing Zhao, Xiaofeng Huang, Yun Ding, Wanjing Ma, Zhongjun Bromodomain Containing Proteins Humans Animals Cell Cycle Proteins Antineoplastic Agents Colorectal Neoplasms Transcription Factors Mice Administration, Oral Cell Proliferation Structure-Activity Relationship Drug Discovery Pyridones Drug Screening Assays, Antitumor Dose-Response Relationship, Drug Molecular Structure Biological Availability Mice, Nude Neoplasms, Experimental Colorectal cancer (CRC) remains a major clinical burden with limited durable responses. Given reports implicating Bromodomain-containing protein 4 (BRD4) in CRC proliferation and therapy resistance, more potent BRD4-targeting agents with proven in-vivo activity are needed. Through virtual screening followed by structure-guided chemical modification, we identified H5 as a BRD4 inhibitor. In biochemical assays, H5 shows IC = 7.9 ± 0.5 nM, outperforming JQ-1 (IC = 33.0 ± 1.0 nM) by 4-fold. Molecular dynamics simulations indicate that H5 engages BRD4 via hydrogen bonds with Asn140 and Asp88 and a water-mediated bridge to Gln85. In the HCT-116 xenograft mouse model, oral administration of H5 suppressed tumor growth (TGI = 82 % at 50 mg/kg) and downregulated the BRD4-driven oncoproteins c-MYC and BCL-2. Collectively, H5 emerges as a highly promising BRD4-targeted candidate for colorectal cancer treatment. |
| title | Discovery of an orally bioavailable pyridone-based BRD4 inhibitor with potent antitumor efficacy in colorectal cancer. |
| topic | Bromodomain Containing Proteins Humans Animals Cell Cycle Proteins Antineoplastic Agents Colorectal Neoplasms Transcription Factors Mice Administration, Oral Cell Proliferation Structure-Activity Relationship Drug Discovery Pyridones Drug Screening Assays, Antitumor Dose-Response Relationship, Drug Molecular Structure Biological Availability Mice, Nude Neoplasms, Experimental |
| url | https://pubmed.ncbi.nlm.nih.gov/41544579/ |