1. Liver-targeting chimeras as a potential modality for the treatment of liver diseases.
- Author
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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 PN, Zi M, He Y, and Zhang X
- Subjects
- Animals, Humans, Sorafenib administration & dosage, Sorafenib therapeutic use, Sorafenib pharmacology, Proteolysis drug effects, Cell Line, Tumor, Mice, Nude, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Liver Neoplasms drug therapy, Female, Mice, Inbred BALB C, Thrombocytopenia chemically induced, Thrombocytopenia drug therapy, Liver metabolism, Liver drug effects, Liver Diseases drug therapy, Asialoglycoprotein Receptor metabolism
- 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., Competing Interests: Declaration of competing interest X.Z., Y.H., C.C., Y.P., and X.Y. are inventors of a pending patent application for the development of LIVTACs for the treatment of liver diseases including HCC., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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