Small-Molecule Hydrophobic Tagging: A Promising Strategy of Druglike Technology for Targeted Protein Degradation Miniperspective

被引:39
作者
Xie, Shaowen [1 ]
Zhu, Jingjie [1 ]
Li, Junda [1 ]
Zhan, Feiyan [1 ]
Yao, Hong [1 ]
Xu, Jinyi [1 ]
Xu, Shengtao [1 ,2 ]
机构
[1] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 211198, Jiangsu, Peoples R China
[2] First Peoples Hosp Kunshan, Dept Hepatobiliary Surg, Suzhou 215300, Peoples R China
基金
中国国家自然科学基金;
关键词
ANDROGEN RECEPTOR AR; MEDIATED DEGRADATION; INDUCE DEGRADATION; HIGHLY POTENT; BREAST-CANCER; DISCOVERY; UBIQUITIN; INHIBITOR; DEGRADER; PROTEASOME;
D O I
10.1021/acs.jmedchem.3c00736
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Targetedprotein degradation (TPD) technologies havecatalyzeda paradigm shift in therapeutic strategies and offer innovative avenuesfor drug design. Hydrophobic tags (HyTs) are bifunctional TPD moleculesconsisting of a & DPRIME;lipophilic small-molecule tags & DPRIME; groupand a small-molecule ligand for the target protein. Despite the vastpotential of HyTs, they have received relatively limited attentionas a promising frontier. Leveraging their lower molecular weight andreduced numbers of hydrogen bond donors/acceptors (HBDs/HBAs) in comparisonwith proteolysis-targeting chimeras (PROTACs), HyTs present a compellingapproach for enhancing druglike properties. In this Perspective, weexplore the diverse range of HyT structures and their correspondingdegradation mechanisms, thereby illuminating their broad applicabilityin targeting a diverse array of proteins, including previously elusivetargets. Moreover, we scrutinize the challenges and opportunitiesentailed in developing this technology as a viable and fruitful strategyfor drug discovery.
引用
收藏
页码:10917 / 10933
页数:17
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