关键词: Autophagy-lysosome pathway Proteolysis-targeting chimera Target protein degradation Ubiquitin-proteasome system

Mesh : Humans Proteolysis Neoplasms / drug therapy Biological Availability Antibodies Molecular Weight Proteolysis Targeting Chimera Ubiquitin-Protein Ligases Proteasome Endopeptidase Complex

来  源:   DOI:10.1016/j.pharmthera.2023.108371

Abstract:
Targeted Protein Degradation is an emerging and rapidly developing technique for designing and treating new drugs. With the emergence of a promising class of pharmaceutical molecules, Heterobifunctional Proteolysis-targeting chimeras (PROTACs), TPD has become a powerful tool to completely tackle pathogenic proteins with traditional small molecule inhibitors. However, the conventional PROTACs have gradually exposed potential disadvantages of poor oral bioavailability and pharmacokinetic (PK) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics due to their larger molecular weight and more complex structure than the conventional small-molecule inhibitors. Therefore, 20 years after the concept of PROTAC was proposed, more and more scientists are committed to developing new TPD technology to overcome its defects. And several new technologies and means have been explored based on \"PROTAC\" to target \"undruggable proteins\". Here, we aim to comprehensively summarize and profoundly analyze the research progress of targeted protein degradation based on PROTAC targeting the degradation of \"undruggable\" targets. In order to clarify the significance of emerging and highly effective strategies based PROTACs in the treatment of various diseases especially in overcoming drug resistance in cancer, we will focus on the molecular structure, action mechanism, design concepts, development advantages and challenges of these emerging methods(e.g., aptamer-PROTAC conjugates, antibody-PROTACs and folate-PROTACs).
摘要:
靶向蛋白质降解是用于新药设计和治疗的新兴且快速发展的技术。随着一类有前途的药物分子的出现,异双功能蛋白水解靶向嵌合体(PROTACs),TPD已成为使用传统小分子抑制剂完全解决致病蛋白的强大工具。然而,传统的PROTACs逐渐暴露了口服生物利用度和药代动力学(PK)和吸收差的潜在缺点,分布,新陈代谢,排泄,和毒性(ADMET)特性,因为它们比常规小分子抑制剂具有更大的分子量和更复杂的结构。因此,PROTAC概念提出20年后,越来越多的科学家致力于开发新的TPD技术来克服其缺陷。已经基于“PROTAC”探索了几种新技术和手段,以靶向“不可药用的蛋白质”。这里,我们旨在全面总结和深入分析基于PROTAC靶向降解“不可药用”靶标的靶向蛋白降解的研究进展。为了阐明基于PROTACs的新兴和高效策略在治疗各种疾病,特别是在克服癌症耐药性方面的重要性,我们将关注分子结构,作用机制,设计理念,这些新兴方法的发展优势和挑战(例如,适体-PROTAC缀合物,抗体-蛋白质和叶酸-蛋白质)。
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