DI 1548(DI 1548) - 药物靶点：DCN1_在研适应症：药物性肝损伤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

DCN1

作用方式

抑制剂

作用机制

DCN1抑制剂(defective in cullin neddylation 1 domain containing 1 inhibitors)

治疗领域

消化系统疾病

在研适应症

药物性肝损伤

非在研适应症-

原研机构

University of Michigan

在研机构

University of Michigan

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C32H47N5O4S

InChIKeyVHEFAXHJOOQBTB-RRPNLBNLSA-N

CAS号2247060-97-3

关联

100 项与 DI 1548 相关的临床结果

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100 项与 DI 1548 相关的转化医学

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100 项与 DI 1548 相关的专利（医药）

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1

项与 DI 1548 相关的文献（医药）

Nature Communications1区 · 综合性期刊

Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

1区 · 综合性期刊

ArticleOA

作者: Shen, Hong ; Stuckey, Jeanne A ; Bernard, Denzil ; Zhou, Haibin ; Liu, Liu ; Chinnaswamy, Krishnapriya ; McEachern, Donna ; Wang, Shaomeng ; Lu, Jianfeng ; Sun, Yi ; Yang, Chao-Yie ; Rui, Liangyou

AbstractCullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2–3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.

100 项与 DI 1548 相关的药物交易

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