2. Academic Validation
  3. Discovery of small molecules for autophagy-lysosome degradation of immune checkpoint proteins

Discovery of small molecules for autophagy-lysosome degradation of immune checkpoint proteins

  • Eur J Med Chem. 2024 Dec 15:280:116958. doi: 10.1016/j.ejmech.2024.116958.
Kaizhen Wang 1,  Zhihao Qi 2,  Jiazheng Guo 2,  Guoqing Shen 2,  Xiang Ni 2,  Sheng Jiang 2,  Kuojun Zhang 3,  Tianyu Wang 4,  Xiangyu Zhang 5
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering and Diagnostic Pharmacy, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: kuojunzhang2017@163.com.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: wangtianyu527@126.com.
  • 5 Department of Biomedical Engineering and Diagnostic Pharmacy, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xiangyu.zhang@cpu.edu.cn.
PMID: 39437574 DOI: 10.1016/j.ejmech.2024.116958
Abstract

Targeted protein degradation (TPD) technologies, particularly proteolysis targeting chimeras (PROTACs), have emerged as a promising branch of targeted therapy. Current ubiquitin-proteasome-dependent TPD technologies are limited to targeting intracellular proteins. Although the blockade of immune checkpoints has achieved great clinical success, most immune checkpoints are transmembrane proteins, which are difficult to be ubiquitinated and degraded by PROTACs. Herein, we developed a novel discovery strategy of bifunctional small molecules, which could mediate autophagy-lysosome degradation of immune checkpoints. F-1 was demonstrated to activate the autophagy-lysosome system, and conjugation of F-1 with inhibitors targeting programmed cell death-ligand 1 (PD-L1) or V-domain Ig suppressor of T-cell activation (VISTA) generated a new class of small molecules that effectively induce the degradation of PD-L1 or VISTA in tumor cells. The most promising PD-L1 degrader B3 significantly induced PD-L1 degradation in RKO cells through the autophagy-lysosome system and exhibited good tumor-inhibiting effects in vivo. Our work could expand the development of degraders targeting immune checkpoints and provide a promising discovery strategy for future autophagy-lysosome targeting degradation technology.

Keywords

Autophagy-lysosome; Cancer immunotherapy; Degrader; PD-1/PD-L1; VISTA.

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