Review
Targeting phosphoinositide 3-kinase—Moving towards therapy

https://doi.org/10.1016/j.bbapap.2007.10.003Get rights and content

Abstract

Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PIK3CA locus coding for PI3Kα, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3Kγ (p110γ) and PI3Kδ (p110δ) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3Kγ have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PKcs) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of > 400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase I) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II).

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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