Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Genetic Evolution & Animal Models, Chinese Academy of Sciences, Kunming, China.
J Control Release. 2024 Oct;374:627-638. doi: 10.1016/j.jconrel.2024.08.044. Epub 2024 Sep 2.
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.
肝脏疾病对全球公共健康构成重大挑战。在药物发现和开发领域，克服“靶内脱靶”效应仍然是各种疾病的一个重大障碍。在这项研究中，我们首创了一种使用蛋白水解靶向嵌合体（PROTAC）分子与肝特异性去唾液酸糖蛋白受体（ASGPR）通过创新的连接子附着策略连接的肝脏靶向嵌合体（LIVTAC）方法，用于在肝脏内精确诱导靶蛋白降解。作为概念验证研究，我们设计了 XZ1606，一种哺乳动物溴结构域和末端外结构域（BET）靶向 LIVTAC 剂，它不仅与索拉非尼联合显示出持久的肿瘤抑制作用（超过 2 个月），而且具有改善的安全性特征，特别是改善了血小板减少症的发生率，血小板减少症是一种常见且严重的与传统 BET 抑制剂相关的靶内剂量限制毒性效应。这些令人鼓舞的结果突出了 LIVTAC 作为一种多功能平台，用于解决广泛的肝脏疾病的潜力。
