PI3K inhibitors

Most 8-selective PI3K inhibitors are derived from IC87114 26, which has an IC50 of 130 nM against PI3K8 and >100-fold selectivity over the a, (3, and y isoforms [99,100], and showed oral efficacy in a neutrophil-driven model of inflammatory arthritis [101]. 

Two well known and isoform unselective PI3K inhibitors are the fungal metabolite wortmannin (compound 7, Fig. 3) and LY294002 (compound 8, Fig. 3). These two compounds have served as powerful research tools for more than a decade to elucidate the role of PI3Ks in human tumorigenesis and evaluate the potential utility of PI3K inhibitors as cancer therapeutics. 

Using wortmannin as a model, broad-spectrum PI3K inhibitors with improved pharmaceutical properties and therapeutic indexes have been reported in recent pubhcations. PWT-458 (compound 10, Fig. 3), which is a pe-gylated derivative of wortmannin, was shown to inhibit PI3K signaling and hold a higher therapeutic index over its parent compoimd when used in sev-... 

In addition to the preceding chemotypes, thiazoles, quinolin-2-ones and cycloalkanothieno-pyrimido-thiazoles [79], azolepyrimidines derivatives, trisubstituted pyrimidines, benzo[fc]thiophenecarboxamides and benzofu-rancarboxamides [80-83], and substituted benzopyranones have also been claimed in different patents as PI3K inhibitors [1]. 

Increased inhibition of proliferation and motiHty by PI3K inhibitors, linked to stronger inhibition of P-AKT... 

Effect of dysbindin-1 overexpression or knockdown on neuronal proteins (a and b), cell viability (c and d), and glutamate release (e and f) in primary cultures of rat cerebrocortical neurons. Overexpression increases Akt phosphorylation and levels of SNAP-25 and synapsin 1, whereas knockdown has the opposite effect (see text Q Sections 2.2.6.53 and Q 2.2.6.S.6 for discussion). The symbols 0 and + in (a) and (b) refer to wild type and expression-altered conditions. GFP green fluorescent protein HK+ high KCL condition HS horse serum LY the PI3K inhibitor LY294002 Adapted with from Numakawa et al. (2004)... 

The anti-apoptotic effect was significantly reduced when the neurons were treated with a PI3K inhibitor (LY294002) able to decrease Akt phosphorylation (Numakawa et al., 2004). It is unclear how dysbindin-1 is able to activate Akt, though there is a predicted Akt binding site in the NTR of dysbindin-1 enabling a direct feedback for activated Akt (see Figure 2.2-2 and Table 2.2-5). 

The inhibitory effects of tea polyphenols on UVB-induced phosphatidylinositol-3-kinase (P13K) activation has been demonstrated in mouse epidermal JB6 Cl 41 cells. Pretreatment of cells with EGCG and TF-3 inhibited UVB-induced PI3K activation. Furthermore, UVB-induced activation of Akt and ribosomal p70S6 kinase (p °S6-K), PI3K downstream effectors, were also attenuated by these tea polyphenols. In addition to LY294002, a PI3K inhibitor, pretreatment with MAP-... 

Doukas, J., Wrasidlo, W., Noronha, G., Dneprovskaia, E., Hood, J., Soil, R. Isoform-selective PI3K inhibitors as novel therapeutics for the treatment of acute myocardial infarction. Biochem. Soc. Trans. 2007, 35, 204-206. 

Membrane activity is accompanied by cellular motility, characterized by extension and withdrawal of cell projections, unaccompanied by significant translational movement. Although this cellular motility program is initiated by MSP, it persists for at least 2 hr without a requirement for continuing MSP stimulation. This conclusion is based on the fact that MSP action is dependent on PI3K, and can be prevented by prior administration of the PI3K inhibitor wortmannin. However, once MSP induces the cellular motility pattern, addition of wortmannin has no effect. 

PI3K-a Inhibitors, pan-PI3K Inhibitors and Dual mTOR-PI3K-a Inhibitors... 

Due to the homology between PI3K and the PIKKs, most notably mTOR, many PI3K inhibitors also inhibit mTOR. Two prototypical PI3K inhibitors have been used extensively as pharmacological tools the natural product, irreversible inhibitor wortmannin ((38), Figure 6.16) and the reversible inhibitor LY294002 (40), a derivative of the natural product quercetin. 

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