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

Chen, Chuanjie, Pan, Yongzhang, Yang, Xiaoyu, Li, Huiqin, Cai, Xinhui, He, Shengyuan, Wang, Qiong, Yang, Yiwen, Zheng, Runzi, Li, Huiwen, Yuan, Shengjie, Dong, Xin, Samarawickrama, Priyadarshani Nadeeshika, Zi, Meiting, He, Yonghan, Zhang, Xuan·2024·Journal of Controlled Release
DOI 10.1016/j.jconrel.2024.08.044
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Abstract

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.

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  • LIVTACs conjugated with triantennary N-acetylgalactosamine (tri-GalNAc) enable selective delivery to hepatocytes via asialoglycoprotein receptor (ASGPR)-mediated endocytosis, increasing local drug concentration while reducing systemic exposure.

    “Liver-Targeting Chimeras (LIVTACs) conjugated with triantennary N-acetylgalactosamine (tri-GalNAc) enable selective delivery to hepatocytes via the asialoglycoprotein receptor (ASGPR)–mediated endocytosis, increasing local drug concentration while reducing systemic exposure”

    From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [92]

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Metadata

Authors
Chen, C., Pan, Y., Yang, X., Li, H., Cai, X., He, S., Wang, Q., Yang, Y., Zheng, R., Li, H., Yuan, S., Dong, X., Samarawickrama, P. N., Zi, M., He, Y., & Zhang, X.
Venue
Journal of Controlled Release
Publisher
Elsevier BV
Published
2024-10
Volume
374
Pages
627-638
ISSN
0168-3659
DOI
10.1016/j.jconrel.2024.08.044
Cited by
25
References
9
Language
en
Licence
Funders
  • National Natural Science Foundation of China (22277131, 8217155 8)
  • Chinese Academy of Sciences
  • National Key Research and Development Program of China (2023YFC3603300)

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