Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation,Journal of the American Chemical Society

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Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2022-11-23 , DOI: 10.1021/jacs.2c08367
Jiwei Zheng ₁ , Wanyi He _{1,

2} , Jing Li _{1,

2} , Xuejia Feng ₁ , Yanyan Li _{1,

3} , Binghua Cheng _{1,

3} , Yimin Zhou ₁ , Meiqing Li ₁ , Ke Liu ₁ , Ximing Shao ₁ , Jianchao Zhang ₄ , Hongchang Li _{1,

3} , Liang Chen _{1,

3} , Lijing Fang _{1,

3}

Affiliation

As effective ways to regulate protein levels, targeted protein degradation technologies have attracted great attention in recent years. Here, we established a novel integrin-facilitated lysosomal degradation (IFLD) strategy to degrade extracellular and cell membrane proteins using bifunctional compounds as molecular degraders. By conjugation of a target protein-binding ligand with an integrin-recognition ligand, the resulting molecular degrader proved to be highly efficient to induce the internalization and subsequent degradation of extracellular or cell membrane proteins in an integrin- and lysosome-dependent manner. As demonstrated in the development of BMS-L1-RGD, which is an efficient programmed death-ligand 1 (PD-L1) degrader validated both in vitro and in vivo, the IFLD strategy expands the toolbox for regulation of secreted and membrane-associated proteins and thus has great potential to be applied in chemical biology and drug discovery.

中文翻译：

双功能化合物作为整合素促进靶向蛋白质降解的分子降解剂

作为调节蛋白质水平的有效方法，靶向蛋白质降解技术近年来备受关注。在这里，我们建立了一种新的整合素促进溶酶体降解 (IFLD) 策略，使用双功能化合物作为分子降解剂来降解细胞外和细胞膜蛋白。通过将靶蛋白结合配体与整合素识别配体结合，所得分子降解剂被证明能够以整合素和溶酶体依赖性方式高效诱导细胞外或细胞膜蛋白的内化和后续降解。正如 BMS-L1-RGD 的开发所证明的那样，它是一种在体外和体内都经过验证的高效程序性死亡配体 1 (PD-L1) 降解剂, IFLD 策略扩展了调节分泌蛋白和膜相关蛋白的工具箱，因此在化学生物学和药物发现中具有巨大的应用潜力。

更新日期：2022-11-23

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