Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation
Jiwei Zheng, Wanyi He, Jing Li, Xuejia Feng, Yanyan Li, Binghua Cheng, Yimin Zhou, Meiqing Li, Ke Liu, Ximing Shao, Jianchao Zhang, Hongchang Li, Liang Chen, Lijing Fang
Abstract
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.