Target Identification of Lagunamide A

Lagunamide A is a biologically active natural product with a yet unidentified molecular mode of action. Cellular studies revealed that lagunamide A is a potent inhibitor of cancer cell proliferation, promotes apoptosis and causes mitochondrial dysfunction. To decipher the cellular mechanism responsible for these effects, we utilized chemical proteomics and identified EYA3 as a target of lagunamide A. EYA3 was functionally validated via knockout and its role for the anti-proliferative and pro-apoptotic effects of lagunamide A was confirmed. As EYA3 turned out to be important for DNA damage repair, we showed that lagunamide A sensitized tumor cells to treatment with the drug doxorubicin highlighting a putative therapeutic strategy.