Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation

J Am Chem Soc. 2022 Dec 7;144(48):21831-21836. doi: 10.1021/jacs.2c08367. Epub 2022 Nov 23.

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.

MeSH terms

  • Integrins*
  • Ligands
  • Proteolysis

Substances

  • Integrins
  • Ligands