Bifunctional Compound for Targeted Degradation of the Immune Checkpoint Protein PD-L1
Received date: 2024-02-01
Online published: 2024-05-09
Supported by
National Natural Science Foundation of China(22177015); Natural Science Foundation of Jiangsu Province(BK20211334); Shenzhen Science and Technology Program(JCYJ20220818101404010); Shenzhen Science and Technology Program(JCYJ20220818100412028)
Programmed death ligand 1 (PD-L1) is a protein overexpressed in numerous tumor cells as an essential immune checkpoint that can facilitate immune escape of tumor cells through binding to PD-1 on T cells. Compared to antibody drugs targeting PD-L1 or PD-1, which are limited in clinical application due to their immunogenicity, high cost and low oral bioavailability, small molecule inhibitors exhibit better tissue and tumor penetration ability, as well as higher bioavailability. However, traditional small molecule inhibitors often face drug resistance issues and are difficult to inhibit protein-protein interactions. Targeted protein degradation (TPD) technologies achieve a more comprehensive suppression of protein activity by degrading the target protein, thereby eliminating its functions entirely. The strategy not only reduces the drug resistance but also enhances the therapeutic efficacy. In the previous study, we have developed the integrin-facilitated lysosome degradation (IFLD) strategy to degrade extracellular and cell membrane proteins by using bifunctional compounds containing a target protein-binding domain, and a cyclic RGD peptide as the integrin-binding domain, connected via a linker. The cyclic RGD peptide, which incorporates the sequence arginine-glycine-aspartic acid (RGD), has been extensively employed for the development of targeted drug delivery systems. It specifically recognizes the integrin αvβ3, which is overexpressed in a variety of tumor cells and plays a significant role in tumor-targeted drug delivery. Considering the instability of the RGD peptide, we designed and synthesized a small molecule compound, Gua-Azide, in this study to mimick the RGD (Arg-Gly-Asp) peptide to bind with αvβ3 integrin. Subsequently, we constructed a new IFLD degrader targeting PD-L1, BMS-Gua, through the conjugation of Gua-Azide with BMS-8, a small molecule with high binding affinity to PD-L1, by using click chemistry. The western blotting and immunofluorescence analysis verified that BMS-Gua, a bifunctional molecule degrader, could effectively induce the endocytosis and lysosomal degradation of PD-L1 through an integrin-dependent pathway, warranting further investigation for the development of tumor immunotherapy drugs.
Congli Chen , Huaihuai Shi , Rui Hao , Lijing Fang , Huadong Xu . Bifunctional Compound for Targeted Degradation of the Immune Checkpoint Protein PD-L1[J]. Acta Chimica Sinica, 2024 , 82(6) : 613 -620 . DOI: 10.6023/A24020042
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