Transforming growth factor-β-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that activates JNK/p38 and NF-κB pro-inflammatory signaling pathways. (5Z)-7-Oxo zeaenol is a natural resorcylic lactone derived from fungi that selectively inhibits purified TAK1 (IC50 = 8.1 nM when co-expressed with the TAK1-binding protein) without significantly affecting the kinase activities of other MAPKKK family members (IC50 = 411 nM for MEK1). In cells, (5Z)-7-oxo zeaenol is reported to irreversibly block IL-1-induced activation of TAK1, NF-κB, and JNK/p38 with IC50 values of 65-83 nM. (5Z)-7-Oxo zeaenol has also been shown to inhibit IL-1-induced COX-2 production in cells and to relieve ear swelling induced by picryl chloride in a mouse model of COX-2-mediated inflammation. This compound has been found to sensitize cells to TRAIL- and TNF-α-induced apoptosis in vitro.
