The PI3K inhibitor arsenal: choose your weapon!

被引:76
作者
Crabbe, Tom [1 ]
Welham, Melanie J.
Ward, Stephen G.
机构
[1] Univ Bath, Inflammatory Cell Biol Lab, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
[2] Univ Bath, Mol Signalling Lab, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
[3] UCB Celltech, Slough SL1 4EN, Berks, England
基金
英国生物技术与生命科学研究理事会;
关键词
D O I
10.1016/j.tibs.2007.09.001
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
Owing to its widespread activation in inflammation and cancer, a growing appreciation of the therapeutic potential of inhibitors of the phosphoinositide 3-kinase (PI3K) pathway has stimulated intense interest in compounds with suitable pharmacological profiles. These are primarily directed toward PI3K itself. However, as class I PI3Ks are also essential for a range of normal physiological processes, broad spectrum PI3K inhibition could be poorly tolerated. In recent years, patents describing a new generation of PI3K inhibitors have started to appear, with a particular focus on the development of compounds with enhanced isoform selectivity for use as anti-cancer and anti-inflammatory therapies. However, challenges remain for the efforts to pharmacologically target this enzyme family in a successful manner.
引用
收藏
页码:450 / 456
页数:7
相关论文
共 65 条
[41]   High frequency of mutations of the PIK3CA gene in human cancers [J].
Samuels, Y ;
Wang, ZH ;
Bardelli, A ;
Silliman, N ;
Ptak, J ;
Szabo, S ;
Yan, H ;
Gazdar, A ;
Powell, DM ;
Riggins, GJ ;
Willson, JKV ;
Markowitz, S ;
Kinzler, KW ;
Vogelstein, B ;
Velculescu, VE .
SCIENCE, 2004, 304 (5670) :554-554
[42]   Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration [J].
Sasaki, T ;
Irie-Sasaki, J ;
Jones, RG ;
Oliveira-dos-Santos, AJ ;
Stanford, WL ;
Bolon, B ;
Wakeham, A ;
Itie, A ;
Bouchard, D ;
Kozieradzki, I ;
Joza, N ;
Mak, TW ;
Ohashi, PS ;
Suzuki, A ;
Penninger, JM .
SCIENCE, 2000, 287 (5455) :1040-1046
[43]   SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling [J].
Shinohara, M ;
Terada, Y ;
Iwamatsu, A ;
Shinohara, A ;
Mochizuki, N ;
Higuchi, M ;
Gotoh, Y ;
Ihara, S ;
Nagata, S ;
Itoh, H ;
Fukui, Y ;
Jessberger, R .
NATURE, 2002, 416 (6882) :759-763
[44]   p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ [J].
Suire, S ;
Coadwell, J ;
Ferguson, GJ ;
Davidson, K ;
Hawkins, P ;
Stephens, L .
CURRENT BIOLOGY, 2005, 15 (06) :566-570
[45]   Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition [J].
Sun, SY ;
Rosenberg, LM ;
Wang, XR ;
Zhou, ZM ;
Yue, P ;
Fu, H ;
Khuri, FR .
CANCER RESEARCH, 2005, 65 (16) :7052-7058
[46]  
Tamura N, 2006, ARTHRITIS RHEUM, V54, pS413
[47]   Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases [J].
Thomas, MJ ;
Smith, A ;
Head, DH ;
Milne, L ;
Nicholls, A ;
Pearce, W ;
Vanhaesebroeck, B ;
Wymann, MP ;
Hirsch, E ;
Trifilieff, A ;
Walker, C ;
Finan, P ;
Westwick, J .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2005, 35 (04) :1283-1291
[48]   Synthesis and function of 3-phosphorylated inositol lipids [J].
Vanhaesebroeck, B ;
Leevers, SJ ;
Ahmadi, K ;
Timms, J ;
Katso, R ;
Driscoll, PC ;
Woscholski, R ;
Parker, PJ ;
Waterfield, MD .
ANNUAL REVIEW OF BIOCHEMISTRY, 2001, 70 :535-602
[49]   Signalling by PI3K isoforms: insights from gene-targeted mice [J].
Vanhaesebroeck, B ;
Ali, K ;
Bilancio, A ;
Geering, B ;
Foukas, LC .
TRENDS IN BIOCHEMICAL SCIENCES, 2005, 30 (04) :194-204
[50]  
VLAHOS CJ, 1994, J BIOL CHEM, V269, P5241