Inhibiting the growth of ovarian cancer cells in vitro and in vivo by a small molecular inhibitor targeting La-RNA interactions
To identify small molecules blocking La-RNA interactions by using structural dynamics, molecular biology, and in vivo efficacy experiments. A docking virtual assay on the Chemdiv database was used to screen La binders, and their affinity were measured by surface plasmon resonance (SPR). A novel fluorescence polarization (FP) assay referring to the binding of La protein and 3'UUUOH was established to identify the inhibitors. Their activity on ovarian cancer cell proliferation, apoptosis and cell cycle were evaluated using Cell Counting Kit 8 (CCK8) and flow cytometry assay, respectively. Their in vivo efficacy against ovarian cancer growth were evaluated in a cell line-derived xenograft (CDX) model of A2780 cells. From a total of 20 compounds with high potential binding activity with La protein, two small molecule compounds 4424-1120 and 8017-5932 with relatively stronger inhibition ability on La-RNA interactions were identified. These two compounds shared the same active centers with hydroxyimidazole and hydroxybenzene to interact with La protein through residues ARG57, GLN20 and GLN136. The in vitro assays showed that 4424-1120 and 8017-5932 effectively cause G0/G1 cell cycle arrest, inhibit cell proliferation, reduce cell invasion and promote apoptosis in ovarian cancer cells. In a CDX model on BALB/C Nude mice, we found that the growth rate of the tumor was inhibited by 4424-1120. Our results demonstrated compound 4424-1120 shows good antitumor activity and safety in vitro and in vivo, and it provides a new idea for the discovery of antitumor lead compounds from small drug-like molecules.