Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis

被引：7

作者：

Chen, Xuetao ^{[1
,2
,3
]}

Wu, Tingting ^{[1
,2
,3
]}

Du, Zhiyan ^{[4
]}

Kang, Wenjing ^{[1
,2
,3
]}

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

Meng, Fanying ^{[1
,2
,3
]}

Liu, Chihong ^{[1
,2
,3
]}

Chen, Yali ^{[1
,2
,3
]}

Bao, Qichao ^{[1
,2
]}

Shen, Jingkang ^{[4
]}

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

Cao, Danyan ^{[4
]}

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

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

机构：

[1] China Pharmaceut Univ, Jiang Su Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

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

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

[4] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 265卷

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

BET; BD1; Bromodomain; Brain-permeable; Multiple sclerosis; DRUG DISCOVERY; TARGETING BROMODOMAIN; POTENT; DERIVATIVES; MODELS; FAMILY; SERIES; BROMO; IDENTIFICATION; OPTIMIZATION;

D O I：

10.1016/j.ejmech.2023.116080

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (Kd = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS.

引用

页数：14