Isolated from the fungi Penicillium funiculosum and Talaromyces wortmannii, wortmannin inhibits Class I, II, and III phosphoinositide 3-kinases (PI3Ks) in vitro with an IC50 around 5 nM, making it markedly more potent than the reversible PI3K probe LY294002.
An electrophilic C20 furan-ring carbon on wortmannin undergoes nucleophilic attack by a conserved active-site lysine in the PI3K catalytic domain, forming an irreversible covalent adduct (and giving wortmannin a short ~10-minute half-life in tissue culture media).
Cell biologists use wortmannin to block insulin/IGF-1–stimulated PI3K/AKT signaling, inhibit Class III PI3K (VPS34)-dependent autophagy initiation, and dissect receptor-mediated endocytosis.