A Keap1-recruiting BRD4 degrader offers a single-molecular polypharmacology approach for the treatment of metabolic dysfunction-associated steatohepatitis

被引：0

作者：

Zhang, Xian ^{[1
,2
,3
]}

Ge, Yuxin ^{[1
,2
,3
]}

Ye, Mengjie ^{[1
,2
,3
]}

Wang, Xiaolu ^{[1
,2
]}

Tong, Yuanyuan ^{[1
,2
]}

Liu, Chihong ^{[1
,2
]}

Xu, Shicheng ^{[1
,2
,3
]}

Zhao, Ziquan ^{[1
,2
,3
]}

You, Qidong ^{[1
,2
,3
]}

Guo, Xiaoke ^{[1
,2
,3
]}

Jiang, Zhengyu ^{[1
,2
,3
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[3] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2025年 / 232卷

基金：

中国国家自然科学基金;

关键词：

MASH; Liver fibrosis; Keap1-Nrf2; BRD4; Protein degradation; EXTRATERMINAL PROTEINS; TARGETING BROMODOMAIN; DRUG DISCOVERY; NRF2; INHIBITORS; PROGRESSION; DETERMINANTS; CHALLENGES; FIBROSIS; DISEASE;

D O I：

10.1016/j.freeradbiomed.2025.02.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) involves multiple pathophysiological processes, including abnormal lipid metabolism, insulin resistance, oxidative stress, endoplasmic reticulum stress, inflammatory response, and fibrosis. These factors interact to form a complex network and the development of synergistic and pleiotropic drug modalities targeting multiple pathogenesis of MASH may have a better therapeutic effect. Herein, the bifunctional proteolytic targeting chimeras (PROTAC) technology was utilized for developing pleiotropic drugs for MASH treatment. We constructed a Keap1-recruiting degrader KB-3 which stabilizes the natural Keap1 target Nrf2 and degrades BRD4 synergistically, exhibiting combined therapeutic advantages against MASH-related pathologies. Experimental results confirmed that KB-3 could effectively alleviate MASH in mice by improving lipid metabolic disorder, enhancing the defense against oxidative stress, reducing inflammation, and delaying the progression of liver fibrosis. Such Keap1-recruiting degrader offering a single-molecular approach with polypharmacology effects may be an attractive strategy for the treatment of multifactorial disease.

引用

页码：15 / 27

页数：13