Phosphatidylinositol-3-kinases inhibitors

Arcaro, A., and Wymann, M. P. (1993). Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor The role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297—301. 

Howes AL, Chiang GG, Lang ES et al (2007) The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 6 2505-2514... 

In an in vitro study, LY294002, a phosphatidylinositol-3-kinase inhibitor, overcame impaired human sperm motility induced by lithium chloride (429). 

B. C. Berk, R. Aebersold and M. A. Corson, Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. J Biol Chem 274, 30101-30108 (1999). 

Yaguchi, S., Fukui, Y., Koshimizu, I., et al. (2006). Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J. Natl Cancer Inst, 98, 545-556. 

In the Chinese hamster ovary cell line ts20, containing a thermosensitive ubiquitin-activating enzyme, El, Sachse et al. (2002) showed that this coat is predominantly present on early endosomes and has a characteristic bilayered appearance in the electron microscope. The coat contains clathrin heavy as well as light chain, but lacks the adaptor complexes API, AP2, and AP3, by which it differs from clathrin coats on endocytic vesicles and recycling endosomes. The coat is insensitive to short incubations with brefeldin A, but disappears in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin. 

Addition of either insulin-like growth factor I or insulin to the serum-free medium prevented rat cerebellar granule cells from developing sensitivity to kainate neurotoxicity whereas brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and nerve growth factor did not (Leski et al. 2000). The phosphatidylinositol 3-kinase inhibitors wort-mannin (10-100 nM) and LY 294002 (0.3-1 pM) aboUshed the protection afforded by IGF-I. 

Ihle NT, Paine-Murrieta G, Berggren MI et al. (2005) The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 4 1349-1357... 

Fujiwara, H., Matsunaga, K., Saito, M., Hagiya, S., Furukawa, K.I., Nakamura, H., and Ohizumi, Y. (2001) Halenaquinone, a novel phosphatidylinositol 3-kinase inhibitor from a marine sponge, induces apotosis in PC12 cells. Eur. J. Pharmacol., 413, 37-45. 

As in the case of sstl, agonist binding to sst4 has and has not been shown to be sensitive to GTP and PTX similarly, inhibition of AC was and was not observed (Demchyshyn et al. 1993 Raynor et al. 1993a Kaupmann et al. 1994 Roosterman et al. 1997). In transfected cells, sst4 was functionally coupled, in a PTX-sensitive fashion, not only to inhibition of AC, but also to activation of arachidonate release and mitogen-activated protein kinase cascade (Bito et al. 1994 Shimizu et al. 1996). These effects were accompanied by the phosphorylation of 85-kDa cytosolic phospholipase A2 and were inhibited by the phosphatidylinositol-3-phosphate kinase inhibitor wortmannin. 

Of the different classes of non-protein kinases, the development of inhibitors of lipid kinases has received by far the most attention. A majority of this work centers on inhibitors of phosphatidylinositol kinases, which reflects the important role that phosphatidylinositols play as second messengers. In this section, we review inhibitors of PI3K and related kinases, as well as inhibitors of other phosphatidyl inositol kinases. We also discuss sphingosine kinase inhibitors and we end this section with a brief summary of inhibitors of other lipid kinases. 

Inostamycin did not inhibit EGF receptor tyrosine kinase, phospholipase C, or phosphatidylinositol kinase, but inhibited CDP-DGzinositol transferase (26). The drug inhibited cellular inositol phosphate formation only when it was added at the same time as labeled inositol. It was found to i.nhibit in vitro CDP-DG inositol transferase activity of the A431 cell membrane, the IC50 being about 0.02 ng/ml. Therefore, inhibition of PI turnover must be due to the inhibition of CDP-DG inositol transferase. Thus, inostamycin is a novel inhibitor of CDP-DG inositol transferase. 

Borst P, Jonkers J, Rottenberg S (2007) What makes tumors multidrug resistant Cell Cycle 6 2782-2787 Caro AA, Cederbaum Al (2006) Role of phosphatidylinositol 3-kinase/AKT as a survival pathway against CYP2El-de-pendent toxicity. J Pharmacol Exp Ther 318 360-372 Chen EL, Xia W, Spector NL (2008) Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors. Clin Cancer Res 14 6730-6734... 

Fig. 4. Effect of membrane-bound phosphatidylinositol-4-phosphate 5-kinase on the LRP uptake. (A) Effect of kinase inhibitors on the internalization of LRP. Assays were performed in the presence of 1 mM H7, 1 mM A3, or 1 M staurosporine, as indicated. (B) Effect of kinase inhibitors on the production of PI4,5P2 by isolated rat liver PMs.

Vlahos CJ, Matter WR, Hui KY, Brown RR. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-l -benzofuran-4-one (LY294002). J Biol Chem 1994 269(7) 5241-5248. 

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