Targeting phosphoinositide 3-kinase - Moving towards therapy

被引:492
作者
Marone, Romina [1 ]
Cmijanovic, Vladimir [2 ]
Giese, Bemd [2 ]
Wymann, Matthias P. [1 ]
机构
[1] Univ Basel, DKBW, Dept Clin & Biol Sci, Ctr Biomed,Inst Biochem & Genet, CH-4058 Basel, Switzerland
[2] Univ Basel, Dept Biomed, Inst Biochem & Genet, CH-4058 Basel, Switzerland
来源
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS | 2008年 / 1784卷 / 01期
关键词
PI3K; cancer; inflammation; allergy; pharmacology; drug development;
D O I
10.1016/j.bbapap.2007.10.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 PlK3CA locus coding for PI3K(x, 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 PI3K gamma (p110 gamma) and PI3K delta (p110 delta) 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 PI3K gamma 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-PKc,) 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 1) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II). (C) 2007 Elsevier B.V. All rights reserved.
引用
收藏
页码:159 / 185
页数:27
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