New Strategy Enables Targeted Degradation of Extracellular and Membrane-associated Proteins
Targeted protein degradation (TPD) technologies including the traditional proteolysis targeting chimeras (PROTACs), the recently reported lysosome-targeting chimeras (LYTACs) and related technologies can specifically identify and degrade the target proteins by hijacking the inherent protein degradation pathways in cells and thus have drawn great attention in medicinal chemistry and chemical biology.
Some of the extracellular and membrane-associated proteins are key agents in cancer, ageing-related diseases, autoimmune disorders, etc., thus are considered to be an important class of drug targets. Therefore, a general strategy to selectively degrade these proteins will offer new opportunities for drug discovery.
Recently, a research team led by Prof. FANG Lijing, Prof. CHEN Liang, and Prof. LI Hongchang from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences, has reported a novel integrin-facilitated lysosomal degradation (IFLD) strategy to degrade extracellular and cell membrane proteins using bifunctional compounds as molecular degraders.
This work was published in Journal of the American Chemical Society on Nov. 24.
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 endocytosis and subsequent lysosomal degradation of extracellular or cell membrane proteins through forming a ternary complex between the target protein and integrin on cell surface.
Since αvβ3 integrin is usually overexpressed in tumors, the IFLD strategy is particularly attractive for targeted degradation of cancer-relevant proteins.
Compared with the antibody-, nanobody-, and aptamer-based technologies, bifunctional molecules possess several advantages as protein degraders such as small size, no immunogenicity, as well as controllable pharmacological and pharmacokinetic properties. And the availability of small molecule inhibitors for many disease-related proteins also provides convenience for the design of IFLD molecular degraders.
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, thus has great potential to be applied in chemical biology and drug discovery.
Integrin-facilitated Lysosomal Degradation (IFLD) Strategy for Extracellular or Membrane Proteins Using Bifunctional Compounds as Molecular Degraders. (Image by Prof. FANG)