1 an enzyme ubiquitously found in all mammalian tissues (1), plays a central role in the anabolic routes of inositol phosphates in vertebrate cells because it phosphorylates the second messenger Ins(1,4,5)P 3 as the starting substrate of these reactions. The IP3K family consists of three isoenzymes referred to as IP3K-A (2-4), IP3K-B (5), and IP3K-C (6) differing in their degree of activation by Ca 2ϩ -CaM, affinity for Ins(1,4,5)P 3 (reviewed in Ref. 7), tissue and intracellular distribution. IP3K-B is expressed in nearly all human tissues and is localized at actin filaments (8, 9) and the endoplasmic reticulum (9, 10) whereas IP3K-A was identified mainly in brain and testis (9, 11) and shows an exclusive F-actin localization (12). IP3K-C is also widely expressed in mammalian cells and in rat it was shown to shuttle actively between nucleus and cytoplasm (13). An additional Ins(1,4,5)P 3 kinase enzyme, inositol polyphosphate multikinase (IPMK), was identified in yeast, rat, man, and plants (14 -18). IPMK exhibits nuclear localization and evidently plays a role in nuclear InsP metabolism (16). In vertebrates, the Ins(1,3,4,5)P 4 product of these enzymes is the starting substrate to be metabolized by different InsP kinases and phosphatases leading to Ins(1,3,4,5,6)P 5 , InsP 6 and the pyrophosphorylated isoforms of InsP 5 and InsP 6 (19,20). InsP 6 is normally the most abundant InsP in eukaryotic cells and appears to be important in several processes; in yeast it is essential for intact vesicle structures (21), mRNA export (22, 23) and is involved in chromatin remodeling (24). For mammalian cells a stimulation of DNA repair (25), endocytosis (26), and exocytosis (27) in pancreatic ␤-cells, Ca 2ϩ channel activity (28, 29), an involvement in synaptic vesicle trafficking (30,31), and other effects were reported for InsP 6 (reviewed in Refs. 19 and 32).To ease studies of the importance of higher InsPs for cell proliferation or other cellular functions in vivo, one possible approach is to block their biosynthesis by pharmacological inhibition of IP3K isoforms and IPMK. Other approaches are knock-out or RNAi experiments shutting down enzymes generating Ins(1,3,4,5)P 4 or higher InsPs. An individual knock-out of IP3K-A in mice resulted in a very weak CNS phenotype in the former case (34). IP3K-B knockout revealed an essential role of the enzyme or its products for T-cell immunity (35). That deletion of the broadly expressed IP3K-B did not generate further phenotypes may be caused by rescue phenomena based on the fact that a total of four enzymes are able to convert Ins(1,4,5)P 3 to Ins(1,3,4,5)P 4 . These considerations led us to start a search for pharmacological IP3K and IPMK inhibitors. We first examined herbal and synthetic compounds belonging to the flavonoids, anthraquinones, coumarins, triphenylmeth-* This work was supported by Grants Ma989 and GRK 336 (to G. W. M.) from the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This articl...

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