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Overexpression of the neuronal InsP 3 kinase-A increases malignancy of different tumor types. Since InsP 3 kinase-A highly selectively binds Ins(1,4,5)P 3 , small molecules competing with Ins(1,4,5)P 3  provide a promising approach for the therapeutic targeting of InsP 3 kinase-A. Based on this consideration, we analyzed the binding mechanism of BIP-4 (2-[3,5-dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]-5, 8-dinitro-1H-benzo[de]isoquinoline-1,3(2H)-dione), a known competitive small-molecule inhibitor of Ins(1,4,5)P 3 . We tested a total of 80 BIP-4 related compounds in biochemical assays. The results of these experiments revealed that neither the nitrophenyl nor the benzisochinoline group inhibited InsP 3 kinase-A activity. Moreover, none of the BIP-4 related compounds competed for Ins(1,4,5)P 3 , demonstrating the high selectivity of BIP-4. To analyze the inhibition mechanism of BIP-4, mutagenesis experiments were performed. The results of these experiments suggest that the nitro groups attached to the benzisochinoline ring compete for binding of Ins(1,4,5)P 3  while the nitrophenyl group is associated with amino acids of the ATP-binding pocket. Our results now offer the possibility to optimize BIP-4 to design specific InsP 3 Kinase-A inhibitors suitable for therapeutic targeting of the enzyme.

Mechanism of BIP-4 mediated inhibition of InsP3Kinase-A