Liver-targeting chimeras as a potential modality for the treatment of liver diseases

被引：0

作者：

Chen, Chuanjie ^{[1
,3
]}

Pan, Yongzhang ^{[2
,3
,4
]}

Yang, Xiaoyu ^{[5
]}

Li, Huiqin ^{[2
,4
]}

Cai, Xinhui ^{[5
]}

He, Shengyuan ^{[1
]}

Wang, Qiong ^{[6
]}

Yang, Yiwen ^{[1
,5
]}

Zheng, Runzi ^{[7
]}

Li, Huiwen ^{[1
,3
]}

Yuan, Shengjie ^{[3
,4
]}

Dong, Xin ^{[2
,4
]}

Samarawickrama, Priyadarshani Nadeeshika ^{[2
,3
,4
]}

Zi, Meiting ^{[2
,4
]}

He, Yonghan ^{[2
,3
,4
]}

Zhang, Xuan ^{[1
,3
,5
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai, Peoples R China

[2] Chinese Acad Sci, Kunming Inst Zool, Key Lab Hlth Aging Res Yunnan Prov, Kunming, Peoples R China

[3] Univ Chinese Acad Sci, Beijing, Peoples R China

[4] Chinese Acad Sci, Key Lab Genet Evolut & Anim Models, Kunming, Peoples R China

[5] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China

[6] Chinese Acad Sci, Kunming Inst Zool, Natl Resource Ctr Nonhuman Primates, Kunming, Peoples R China

[7] Kunming Univ Sci & Technol, Med Sch, Lab Mol Genet Aging & Tumor, Kunming, Peoples R China

来源：

JOURNAL OF CONTROLLED RELEASE | 2024年 / 374卷

基金：

中国国家自然科学基金;

关键词：

ASGPR; BET; Hepatocellular carcinoma; LIVTAC; On-target toxicity; PROTAC; ANTIBODY-MEDIATED DELIVERY; PHARMACOKINETICS; HEPATOCYTES; DEGRADATION; RESISTANCE; CANCER;

D O I：

10.1016/j.jconrel.2024.08.044

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Liver diseases pose significant challenges to global public health. In the realm of drug discovery and development, overcoming 'on-target off-tissue' effects remains a substantial barrier for various diseases. In this study, we have pioneered a Liver-Targeting Chimera (LIVTAC) approach using a proteolysis-targeting chimera (PROTAC) molecule coupled to the liver-specific asialoglycoprotein receptor (ASGPR) through an innovative linker attachment strategy for the precise induction of target protein degradation within the liver. As a proof-of-concept study, we designed XZ1606, a mammalian bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent, which not only demonstrated enduring tumor suppression (over 2 months) in combination with sorafenib but also an improved safety profile, notably ameliorating the incidence of thrombocytopenia, a common and severe on-target dose-limiting toxic effect associated with conventional BET inhibitors. These encouraging results highlight the potential of LIVTAC as a versatile platform for addressing a broad spectrum of liver diseases.

引用

页码：627 / 638

页数：12

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