Journal of controlled release : official journal of the Controlled Release Society · 2024
Liver-targeting chimeras as a potential modality for the treatment of liver diseases.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.