Small-molecule inhibitors of the PI3K signaling network - PubMed (original) (raw)

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Small-molecule inhibitors of the PI3K signaling network

Colleen R McNamara et al. Future Med Chem. 2011 Apr.

Abstract

The phosphoinositide 3-kinase (PI3K) signaling pathway controls a wide variety of cellular processes including cell death and survival, cell migration, protein synthesis and metabolism. Aberrant PI3K-dependent signaling, mediated by Akt kinase, has been implicated in many human diseases including cancer, inflammation, cardiovascular disease and metabolic diseases, making this pathway a principle target for drug development. In this article we will summarize the PI3K signaling network and discuss current strategies for pathway inhibition. We will also explore the importance and emerging relevance of Akt-independent PI3K signaling pathways and discuss attempts being made to harness these pathways by inhibiting the binding of a product of PI3K, phosphatidylinositol-(3,4,5)-trisphosphate, to effector pleckstrin homology domains.

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Figures

Figure 1

Figure 1. Phosphatidylinositol

An inositol headgroup is bound to phosphatidic acid via its 1′-hydroxyl group. Phosphatidic acid is composed of a glycerol backbone with fatty acids bound to carbons-1 and -2 (represented by waves in this graphic) and a phosphate group bound to carbon-3. The 4′- and 5′-hydroxyl groups are phosphorylated in PIP2. PI3K generates PIP3 by phosphorylating the 3′-hydroxyl group.

Figure 2

Figure 2. The phosphinositide-3-kinase/Akt signaling pathway

RTKs, activated in response to growth factor signaling, initiate PI3K signaling. Activated PI3K phosphorylates PIP2 to generate PIP3. Akt and PDK1 then bind to PIP3 via their PH domains and are localized to the plasma membrane. Akt is activated by phosphorylation of Thr-308 by PDK1 and Ser-473 by mTORC2. Activated Akt controls cell death and survival, cell cycle regulation, regulation of protein synthesis, angiogenesis and cell metabolism through activation or inhibition phosphorylations of many downstream substrates. Signaling is terminated when enzymes, such as PTEN, dephosphorylate PIP3. 4EBP1: Eukaryotic initiation factor 4E binding protein 1; Casp9: Caspase 9; FOXO: Forkhead family of transcription factor; GSK3: Glycogen synthase kinase 3; mTORC: Mammalian target of rapamycin (mTOR) complex; P: Phosphate; PDK1: Phosphoinositide-dependent kinase 1; PI3K: Phosphinositide-3-kinase; PIP2: Phosphatidylinositol-4–5-P2; PIP3: Phosphatidylinositol-3–4–5-P3; PTEN: Phosphatase and tensin homolog; Rheb: Ras homolog enriched in brain; RTK: Receptor tyrosine kinase; S6K1: p70S6 kinase; TSC: Tuberous sclerosis complex.

Figure 3

Figure 3

Representative PI3K pathway inhibitors.

Figure 4

Figure 4

Representative lipid-based antagonists of PIP3–PH domain interactions.

Figure 5

Figure 5

Representative nonlipid antagonists of PIP3–PH domain interactions.

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