Liver-targeting chimeras as a potential modality for the treatment of liver diseases
Year: 2024
Type: article
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.
Source: Journal of Controlled Release
Authors: Chuanjie Chen, Yongzhang Pan, Xiaoyu Yang, Huiqin Li, Xinhui Cai, Shengyuan He, Qiong Wang, Yiwen Yang, Runzi Zheng, Huiwen Li, Shengjie Yuan, Xin Dong, Priyadarshani Nadeeshika Samarawickrama, Meiting Zi, Yonghan He, Xuan Zhang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,540
Awards: G2343061799, G7022248600, G8554698105
OpenAlex ID: W4402120375