期刊
CURRENT TOPICS IN MEDICINAL CHEMISTRY
卷 9, 期 8, 页码 738-753出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156802609789044434
关键词
PI3K; inflammation; allergy; asthma; rheumatoid arthritis; COPD
In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3K delta) and gamma (PI3K gamma) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (alpha/beta/gamma/delta) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K delta/gamma lipid kinases are mainly restricted to the hematopoetic system whereas PI3K alpha/beta are ubiquitously expressed, thus raising potential toxicity concerns for chronic indications such as asthma and rheumatoid arthritis. Therefore, the challenge in developing a small molecule inhibitor of PI3K is to define and attain the appropriate isoform selectivity profile. Significant advances in the design of such compounds have been achieved by utilizing x-ray crystal structures of various inhibitors bound to PI3K gamma in conjunction with pharmacophore modeling and high-throughput screening. Herein, we review the history and challenges involved with the discovery of small molecule isoform-specific PI3K inhibitors. Recent progress in the design of selective PI3K delta, PI3K gamma, and PI3K delta/gamma dual inhibitors will be presented.
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