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

Uveal melanoma (UM) represents the predominant ocular malignancy among adults, exhibiting high malignancy and proclivity for liver metastasis. GNAQ and GNA11 encoding G alpha q and G alpha 11 proteins are key genes to drive UM, making the selective inhibition of G alpha q/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 G alpha q/11 proteins and UM cells. Compound F33 emerged as the most favorable candidate, and displayed moderate inhibitory activity against G alpha q/11 proteins (IC50 = 9.4 mu M) and two UM cell lines MP41 (IC50 = 6.7 mu M) and 92.1 (IC50 = 3.7 mu M). Being a small molecule inhibitor of G alpha q/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 G alpha q/11 proteins.