PI3 kinase inhibitors

PC3 Prostate Invasive (EMT) phenotype developed STAT/interferon, P13-kinase, AKT, and integrin signaling PI3-kinase inhibitors blocked invasive cell growth more effectively in 3-D (30)... 

Yu C, Dent P, Grant S. 2002. Pharmacologic PI3 kinase inhibitors interact in a highly synergistic manner with the cyclin-dependent kinase flavopiridol... 

Wyeth (2009) 3-Substituted-lH-indole compounds, their use as MTOR kinase and PI3 kinase inhibitors, and their synthesis. Patent US2009/311217 (Al)... 

Cao, P. Maira, SM., Garcia-Echeverria, C. and Hedley, DW. (2009) Br. J. Cancer, Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xengrafts. 100, 1267-1276. 

Programmed cell death plays an important role during lymphocyte development, by eliminating autoreactive cells, as well as in the effector phase of the immune response, when antigen induced cell death halt cell activation. Several groups have been studied the function of PTEN in the immune response. PTEN heterozygous (PTEN+/-) mutants develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas-deficient mutants. Fas-mediated apoptosis was impaired in Pten+/-mice, and T lymphocytes from these mice show reduced activation-induced cell death and increased proliferation upon activation. PI3-K inhibitors restored Fas responsiveness in PTEN+/- cells. These results indicate that PTEN is an essential mediator of the Fas response and a repressor of autoimmunity, thus implicate the P13-Kinase/Akt pathway in Fas-mediated apoptosis (DiCristofano et al, 1999)... 

The regulation of translation is accomplished in this system via a specific inhibitory protein and an initiation factor of translation. The binding activity of the inhibitor protein is regulated by protein phosphorylation, and thus, by protein kinases. The activity of protein kinases can be regulated in a multitude of ways. A signal initiating from insulin, for example, can activate the PI3-kinase and the Akt kinase pathway (see 6.6.2), resulting in phosphorylation of 4E-BP1. 

Targeted inhibition of clathrin, AP2, epsin, others Metabolic inhibitor Inhibitor of PI3 kinases... 

There seemed to be some hope of identifying such a receptor from the inside out. TNF, by this time taken as animportant endpoint of LPS responses, was synthesized as a result of separate transcriptional and translational activation events. Enhanced TNF gene transcription in myeloid cells followed LPS activation as a result of translocation of NF-/< B to the nucleus (40). Translational activation depended upon de-repression of a UA-rich element in the 3-untranslated region of the TNF mRNA (41). Subsequently, this event required activation of p38 (43), a protein that was first identified because it became phosphorylated in endotoxin-activated macrophages (44). In addition, LPS activated the MAP kinase pathway (45) and PI3 kinase pathway (46-49). The added importance of a tyrosine kinase in LPS signaling was suggested by the fact that tyrosine kinase inhibitors could block signal transduction (50). All attempts to find the critical transmembrane receptor that initiated these events were unsuccessful. 

Figure 6 Effect of hypoxia on the phosphorylation of Akt. PC12 cells were pretreated with either wortmannin (100 nM), a specific inhibitor of PI3-Kinase, or vehicle (0.01% DMSO) for 1 hr prior to exposure to either normoxia (21% O2) or hypoxia (5% O2) for 6 hr. Whole-cell lysates were then immunoblotted for either phospo-Akt (a), total Akt (b), phospho-GSK3 (c), phospho-CREB (d), or EPASl (e). Note that CREB phosphorylation and EPASl phosphorylation and accumulation persist in the presence of wortmannin.

Several recent studies have demonstrated that flavonoids may be potent inhibitors of enzymes, including PTKs, PKC and phosphatidylinositol 3-kinase (PI3-kinase) (16, 17), It has been reported that flavonoids which inhibit PTKs and PKC have 3 4 -OH groups on the B ring, and 5,7-OH groups on the A ring (16, 17). These results suggest that flavonoid structures required for the inhibition of PTKs and PKC are involved in suppressing COX-2 expression. 

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