Arvinas, Inc., 5 Science Park, New Haven, CT 06511, USA.
Arvinas, Inc., 5 Science Park, New Haven, CT 06511, USA.
Cell Chem Biol. 2024 Sep 19;31(9):1688-1698. doi: 10.1016/j.chembiol.2024.08.010.
This minireview explores the burgeoning field of targeted protein degradation (TPD) and its promising applications in neuroscience and clinical development. TPD offers innovative strategies for modulating protein levels, presenting a paradigm shift in small-molecule drug discovery and therapeutic interventions. Importantly, small-molecule protein degraders specifically target and remove pathogenic proteins from central nervous system cells without the drug delivery challenges of genomic and antibody-based modalities. Here, we review recent advancements in TPD technologies, highlight proteolysis targeting chimera (PROTAC) protein degrader molecules with proximity-induced degradation event-driven and iterative pharmacology, provide applications in neuroscience research, and discuss the high potential for translation of TPD into clinical settings.
这篇综述探讨了靶向蛋白降解（TPD）这一新兴领域，以及其在神经科学和临床开发方面的广阔应用前景。TPD 提供了创新的蛋白质水平调节策略，在小分子药物发现和治疗干预方面带来了范式转变。重要的是，小分子蛋白降解剂可特异性地靶向并从中枢神经系统细胞中去除致病蛋白，而无需面对基因组和抗体模式的药物输送挑战。在这里，我们回顾了 TPD 技术的最新进展，强调了具有邻近诱导降解事件驱动和迭代药理学的蛋白水解靶向嵌合体（PROTAC）蛋白降解剂分子，探讨了其在神经科学研究中的应用，并讨论了 TPD 转化为临床应用的巨大潜力。
