Drugging PI3K in cancer: refining targets and therapeutic strategies

被引：179

作者：

Yap, Timothy A. ^{[1
,2
]}

Bjerke, Lynn ^{[1
,3
]}

Clarke, Paul A. ^{[1
]}

Workman, Paul ^{[1
]}

机构：

[1] Inst Canc Res, Div Canc Therapeut, Canc Res UK Canc Therapeut Unit, Sutton SM2 5NG, Surrey, England

[2] Royal Marsden NHS Fdn Trust, Sutton SM2 5PT, Surrey, England

[3] Inst Canc Res, Div Mol Pathol, Sutton SM2 5NG, Surrey, England

来源：

CURRENT OPINION IN PHARMACOLOGY | 2015年 / 23卷

关键词：

PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR; PHASE-I SAFETY; PHOSPHOINOSITIDE; 3-KINASE; BREAST-CANCER; MOLECULAR PHARMACOLOGY; PI3K/MTOR INHIBITOR; ACQUIRED-RESISTANCE; ANTITUMOR-ACTIVITY; DOSE-ESCALATION; PATHWAY;

D O I：

10.1016/j.coph.2015.05.016

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling routes in human cancers, making it a rational and important target for innovative anticancer drug development and precision medicine. The three main classes of PI3K inhibitors currently in clinical testing comprise dual pan-Class I PI3K/mTOR inhibitors, pan-Class I PI3K inhibitors lacking significant mTOR activity and isoform-selective PI3K inhibitors. A major step forward in recent years is the progression of over 30 small molecule PI3K inhibitors into clinical trials and the first regulatory approval of the PI3K delta inhibitor idelalisib for multiple B-cell malignancies. This review article focuses on the progress made in the discovery and development of novel PI3K inhibitors, with an emphasis on antitumour activity and tolerability profiles for agents that have entered clinical trials. We also discuss the key issues of drug resistance, patient selection approaches and rational targeted combinations. Finally, we envision the future development and use of PI3K inhibitors for the treatment of patients with a range of malignancies.

引用

页码：98 / 107

页数：10

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