Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewTargeting phosphoinositide 3-kinase—Moving towards therapy
Section snippets
Introduction to phosphoinositide 3-kinases (PI3Ks)
Phosphoinositide 3-kinases (PI3Ks) were early on identified as lipid kinases associated with viral oncogens [1], [2], [3], and for the last 20 years, the connection between cancer and PI3K has been further substantiated [4], [5], [6]. PI3Ks have since been recognized to modulate a wide range of cellular activities, and to be central to the growth and metabolic control. Although not discussed in depth in the following, early work in model organisms, like D. melanogaster [7], [8], C. elegans [9],
The phosphoinositide 3-kinase (PI3K) family
PI3Ks are a family of enzymes, which phosphorylate the 3′-OH position of the inositol ring of phosphoinositides. They have been divided into three classes on the basis of structural features and in vitro lipid substrate specificity (Fig. 1, Table 1; and [14], [15]).
Class I PI3Ks form heterodimers, which consist of one of the four closely related ∼ 110 kDa catalytic subunits, and an associated regulatory subunit belonging to two distinct families. In vitro they are capable to convert PtdIns to
PI3K class I activation and signaling
The PI3K pathway is a key signaling transduction cascade controlling the regulation of cell growth, proliferation, survival as well as cell migration. PI3Ks are activated by a wide variety of different stimuli including growth factors, inflammatory mediators, hormones, neurotransmitters, and immunoglobulins and antigens [18], [47]. The class IA PI3K isoforms PI3Kα, β and δ, are all bound to one of the p85/p55/p50 regulatory subunits, which all harbor two SH2 domains that bind with high affinity
PI3Ks in disease
As described above, activation of the PI3K/PKB signaling cascade has a positive effect on cell growth, survival and proliferation. Constitutive up-regulation of PI3K signaling can have a deleterious effect on cells leading to uncontrolled proliferation, enhanced migration and adhesion-independent growth. These events favor not only the formation of malignant tumors, but also the development of inflammatory and autoimmune disease [5], [6], [13].
Validation and targeting of class I PI3Ks with low-molecular weight chemical compounds
Genetic approaches as described above have partially validated some individual PI3K isoforms as drug targets in complex disease conditions. For some PI3K isoforms, this was hampered by embryonic lethality (e.g. for PI3Kα and PI3Kβ “knock-out” mice [74], [75]), potential developmental compensation and overlapping functions of other PI3K isoforms. Initially, validation of PI3Ks as drug targets was attempted using wortmannin and LY294002, which both target a broad range PI3K-related enzymes [18],
Conclusions and outlook
The pharmaceutical development of PI3K inhibitors has made a great leap forward during the last 5 years. Promising molecules have entered clinical trials for cancer therapy, inflammation and coronary heart disease. As summarized in Fig. 6, first inhibitors with some isoform specificity have been lanced. While inhibitor selectivity is often impressive when assessed in vitro, the in vivo selectivity, potency and efficacy often require further optimization, especially for the treatment of chronic
Acknowledgements
We thank Poppy Fotiadou, Nathanael S. Gray, and David Woodmansee for the critical reading of the manuscript, and Natasa Cmiljanovic for data retrieval, and Federica Marone for help with graphical work. This work was supported by the Oncosuisse grant 01924-08-2006, the Swiss National Science Foundation, grants 3100A0-109718 and NCH1524 and the EU FP6 programme LSHG-CT-2003-502935.
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