2. Academic Validation
  3. Design, synthesis and evaluation of quinazoline derivatives as Gαq/11 proteins inhibitors against uveal melanoma

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.
Guangjin Fan 1,  Lu Liu 1,  Jia Ye 1,  Wei Xiao 2,  Xiao-Feng Xiong 3
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006 Guangzhou, Guangdong, PR China.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060 Guangzhou, Guangdong, China. Electronic address: [email protected].
  • 3 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006 Guangzhou, Guangdong, PR China. Electronic address: [email protected].
PMID: 38043397 DOI: 10.1016/j.bioorg.2023.107005
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.

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