Alantolactone is a natural product that potently inhibits YAP1/TAZ via promotion of ROS accumulation
YAP1 and its paralogue TAZ play pivotal roles in cell proliferation, migration and invasion, and abnormal activation of these TEAD transcriptional co-activators is found in diverse cancers in humans and mice. Targeting YAP1/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase
... system to monitor YAP1/TAZ-TEAD transcriptional activity in cells. Among 29,049 low-molecular-weight compounds screened, we obtained 9 hits, and the 4 of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS-induced LATS kinase activities and thus YAP1/TAZ phosphorylation. Phosphorylated YAP1/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT-treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS-YAP pathway driving tumor cell growth and so may be a potent anti-cancer drug.