Abstract
Signaling pathways regulated by the phosphoinositide 3-kinase (PI3K) enzymes have a well-established role in cancer development and progression. Over the past 30 years, the therapeutic potential of targeting this pathway has been well recognized, and this has led to the development of a multitude of drugs, some of which have progressed into clinical trials, with few of them currently approved for use in specific cancer settings. While many inhibitors compete with ATP, hence preventing the catalytic activity of the kinases directly, a deep understanding of the mechanisms of PI3K-dependent activation of its downstream effectors led to the development of additional strategies to prevent the initiation of this signaling pathway. This review summarizes previously published studies that led to the identification of inositol polyphosphates as promising parent molecules to design novel inhibitors of PI3K-dependent signals. We focus our attention on the inhibition of protein–membrane interactions mediated by binding of pleckstrin homology domains and phosphoinositides that we proposed 20 years ago as a novel therapeutic strategy.
Highlights
Phosphoinositides consist of a water-soluble inositol head linked to a diacylglycerol by a phosphodiester linkage (Figure 1) [1]
While many of the phosphoinositide 3-kinase (PI3K)/Akt inhibitors compete with ATP, preventing the catalytic activity of the kinases directly, identification of the pleckstrin homology (PH) domain-mediated mechanisms of activation paved the road to the development of alternative strategies to inhibit Akt and its signaling pathways
Akt PH domain was found to bind to Inositol 1,3,4,5,6-pentakisphosphate (InsP5), and to a slightly lesser extent to Inositol 1,4,5,6-tetrakisphosphate (Ins(1,4,5,6)P4) [58]. We proposed that such a feature could be exploited as an alternative strategy to block the interaction between phosphoinositides and PH domains, as water-soluble inositol polyphosphates could be delivered intracellularly and compete with phosphoinositides for PH domain binding [61]
Summary
Phosphoinositides consist of a water-soluble inositol head linked to a diacylglycerol by a phosphodiester linkage (Figure 1) [1]. PtdIns (3,4,5)P3 is one of the three lipid products of a family of enzymes named Phosphoinositide 3-kinases (PI3Ks) because of their ability to catalyze phosphorylation at the inositol 3 position within selective phosphoinositides [16,17] Their substrate specificity, together with their structure, has provided the basis for grouping the eight mammalian PI3Ks into three classes [18,19,20]. Considering its ability to regulate a vast array of cellular functions, it is not surprising that Akt activation is tightly regulated, mainly via a strict temporal regulation of PtdIns(3,4,5)P3 levels This is the result of a fine balance between class I PI3K activation and the action of the enzyme Phosphatase and tensin homolog (PTEN), which dephosphorylates PtdIns(3,4,5)P3 at its 3-position, converting it back to PtdIns(4,5)P2 (Figure 3) [29]. Studies to identify novel strategies to block this pathway more efficiently and overcome these limitations are still required
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