Combinatorial Targeting\nof Common Docking and ATP\nBinding Sites on Mps1 MAPK for Management of Pathogenic Fungi

Resistance in pathogenic\nfungi necessitates the development\nof\nfungicides with new mechanisms of action. The Mps1 MAPK of Magnaporthe oryzae, the pathogen of rice blast disease,\nhas been shown to be a molecular target for fungicide research. Here,\nwe present compound TAK-733 that interacts with the common docking\n(CD) site of Mps1 and can be used in combination with ATP-competitive\ninhibitors. We initially identified compounds PLX-4720 and TAK-733\nthat interact with Mps1. Subsequent assays show that PLX-4720 is an\nATP-competitive inhibitor, whereas TAK-733 binds to the CD site of\nMps1an interaction site for its MAPKKbut not to the\nATP-binding pocket as it does in the kinase MEK1. In vivo assays demonstrated\nthat TAK-733 exhibits combinational effects with ATP-competitive inhibitors\nPLX-4720 and A378–0. Collectively, we present TAK-733 as having\na new mechanism of action suitable for combinational application with\nATP-competitive inhibitors in the management of pathogenic fungi.