Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou 215300, China.
J Med Chem. 2023 Aug 24;66(16):10917-10933. doi: 10.1021/acs.jmedchem.3c00736. Epub 2023 Aug 3.
Targeted protein degradation (TPD) technologies have catalyzed a paradigm shift in therapeutic strategies and offer innovative avenues for drug design. Hydrophobic tags (HyTs) are bifunctional TPD molecules consisting of a ″lipophilic small-molecule tags″ group and a small-molecule ligand for the target protein. Despite the vast potential of HyTs, they have received relatively limited attention as a promising frontier. Leveraging their lower molecular weight and reduced numbers of hydrogen bond donors/acceptors (HBDs/HBAs) in comparison with proteolysis-targeting chimeras (PROTACs), HyTs present a compelling approach for enhancing druglike properties. In this Perspective, we explore the diverse range of HyT structures and their corresponding degradation mechanisms, thereby illuminating their broad applicability in targeting a diverse array of proteins, including previously elusive targets. Moreover, we scrutinize the challenges and opportunities entailed in developing this technology as a viable and fruitful strategy for drug discovery.
靶向蛋白降解（TPD）技术推动了治疗策略的范式转变，为药物设计提供了创新途径。疏水标签（HyT）是一种双功能的 TPD 分子，由“亲脂小分子标签”基团和靶向蛋白的小分子配体组成。尽管 HyT 具有巨大的潜力，但作为一个有前途的前沿领域，它们受到的关注相对较少。与蛋白水解靶向嵌合体（PROTACs）相比，HyT 的分子量更小，氢键供体/受体（HBDs/HBAs）的数量更少，因此它们是增强类药性的一种很有吸引力的方法。在本观点中，我们探讨了各种 HyT 结构及其相应的降解机制，从而阐明了它们在靶向各种蛋白质（包括以前难以靶向的目标）方面的广泛适用性。此外，我们还仔细研究了开发这项技术所面临的挑战和机遇，将其作为一种可行且富有成效的药物发现策略。
