Regulation of post-translational modification of PD-L1 and associated opportunities for novel small-molecule therapeutics

Future Med Chem. 2024 Aug 2;16(15):1583-1599. doi: 10.1080/17568919.2024.2366146. Epub 2024 Jul 1.

Abstract

PD-L1 is overexpressed on the surface of tumor cells and binds to PD-1, resulting in tumor immune escape. Therapeutic strategies to target the PD-1/PD-L1 pathway involve blocking the binding. Immune checkpoint inhibitors have limited efficacy against tumors because PD-L1 is also present in the cytoplasm. PD-L1 of post-translational modifications (PTMs) have uncovered numerous mechanisms contributing to carcinogenesis and have identified potential therapeutic targets. Therefore, small molecule inhibitors can block crucial carcinogenic signaling pathways, making them a potential therapeutic option. To better develop small molecule inhibitors, we have summarized the PTMs of PD-L1. This review discusses the regulatory mechanisms of small molecule inhibitors in carcinogenesis and explore their potential applications, proposing a novel approach for tumor immunotherapy based on PD-L1 PTM.

Keywords: N-linked glycosylation; PD-L1; PTMs; acetylation; methylation; palmitoylation; phosphorylation; ubiquitination.

Plain language summary

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Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • B7-H1 Antigen* / antagonists & inhibitors
  • B7-H1 Antigen* / metabolism
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • Protein Processing, Post-Translational* / drug effects
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology

Substances

  • B7-H1 Antigen
  • Small Molecule Libraries
  • CD274 protein, human
  • Antineoplastic Agents