Purine-based inhibitors of inositol-1,4,5-trisphosphate-3-kinase.

Inositol 1,4,5-trisphosphate 3-kinase (IP3K) catalyzes the adenosine triphosphate (ATP) dependent phosphorylation of inositol 1,4,5-trisphosphate (IP3) to inositol 1,3,4,5-tetrakisphosphate (IP4) and plays an important role in the regulation of intracellular calcium concentration. IP3 is a well-known second messenger that stimulates intracellular calcium mobilization, which is in turn responsible for numerous intracellular responses related to fertilization, cell growth, and secretion. Production of IP3 is triggered by cell surface receptor activation by extracellular ligands that act downstream of both the receptor tyrosine kinases and the guanosine triphosphate binding protein (G-protein) coupled receptors. In addition, it has been suggested that IP4, the product of the IP3K-catalyzed reaction, also serves as a second messenger that potentiates IP3 as a calcium oscillation regulator through inhibition of hydrolysis of IP3 (Figure 1) and other mechanisms. Consequently, a specific inhibitor for IP3K will be a useful tool to study the role of this enzyme in transmembrane signal