Design, synthesis and evaluation of quinazoline derivatives as Gαq/11 proteins inhibitors against uveal melanoma

Bioorg Chem. 2024 Feb:143:107005. doi: 10.1016/j.bioorg.2023.107005. Epub 2023 Nov 29.

Abstract

Uveal melanoma (UM) represents the predominant ocular malignancy among adults, exhibiting high malignancy and proclivity for liver metastasis. GNAQ and GNA11 encoding Gαq and Gα11 proteins are key genes to drive UM, making the selective inhibition of Gαq/11 proteins to be a potential therapeutic approach for combating UM. In this study, forty-six quinazoline derivatives were designed, synthesized, and assessed for their ability to inhibit Gαq/11 proteins and UM cells. Compound F33 emerged as the most favorable candidate, and displayed moderate inhibitory activity against Gαq/11 proteins (IC50 = 9.4 μM) and two UM cell lines MP41 (IC50 = 6.7 μM) and 92.1 (IC50 = 3.7 μM). Being a small molecule inhibitor of Gαq/11 proteins, F33 could effectively suppress the activation of downstream signaling pathways in a dose-dependent manner, and significantly inhibits UM in vitro.F33 represents a promising lead compound for developing therapeutics for UM by targeting Gαq/11 proteins.

Keywords: Anti-tumor effect; Gαq/11 proteins inhibitors; Quinazoline derivatives; Structure-activity relationship studies; Target verification.

MeSH terms

  • Cell Line, Tumor
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Melanoma* / pathology
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Signal Transduction
  • Uveal Neoplasms* / drug therapy
  • Uveal Neoplasms* / genetics
  • Uveal Neoplasms* / metabolism

Substances

  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Quinazolines

Supplementary concepts

  • Uveal melanoma