Discovery of natural flavanones as potential PRMT4 inhibitors with antiproliferative activity against colorectal cancer cells

Protein arginine N-methyltransferase 4 (PRMT4) has been a novel target to discover anticancer drugs, and PRMT4 inhibitors offer a promising option for the treatment of colorectal cancer. In this work, a series of natural flavanones were evaluated for their inhibitory activity against PRMT4. Among them, Lespedezaflavanone H was a potent and selective PRMT4 inhibitor with an IC 50 value of 1.73 µM. Lespedezaflavanone H was predicted to form hydrogen bonds with ASN-265 and ARG-267 of PRMT4, as revealed by molecular docking. Chemical descriptors and molecular electrostatic potential analysis of Lespedezaflavanone H were deeply investigated. Molecular dynamics simulations demonstrated that the complex between PRMT4 and Lespedezaflavanone H maintained a stable binding mode. Importantly, Lespedezaflavanone H inhibited the proliferation of colorectal cancer cell lines RKO, SW620, COLO 205, and LS180 with IC 50 values of 3.93, 2.32, 5.68, and 11.26 µM, respectively. To the best of our knowledge, this is the first report that Lespedezaflavanone H acts as a PRMT4 inhibitor and exhibits antiproliferative activity against colorectal cancer cells.