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

被引：50

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 16期

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

页码：10917 / 10933

页数：17

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