Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity.

Phosphoinositide-3-kinase is a pivotal protein involved in a wide variety of signaling cascades and there has been a great deal of interest in the development of potent and selective inhibitors of this enzyme. In this review, the potency and selectivity of the known inhibitors is presented along with key structural information that helps rationalize the observed trends.

[1]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[2]  M. Waterfield,et al.  PI3-kinase inhibition: a target for drug development? , 2000, Molecular medicine today.

[3]  K. Cengel,et al.  Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. , 2008, Cancer research.

[4]  Joe W. Gray,et al.  PIK3CA is implicated as an oncogene in ovarian cancer , 1999, Nature Genetics.

[5]  M. Herlyn,et al.  Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity. , 2008, ACS chemical biology.

[6]  M. Waterfield,et al.  Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors. , 2006, Bioorganic & medicinal chemistry.

[7]  D. Staunton,et al.  Selective role of PI3Kδ in neutrophil inflammatory responses , 2003 .

[8]  Leland J. Gershell,et al.  Selective anticancer drugs , 2002, Nature Reviews Drug Discovery.

[9]  R. Jaffe,et al.  Phosphatidylinostol 3-Kinase Mediates Angiogenesis and Vascular Permeability Associated with Ovarian Carcinoma , 2005, Clinical Cancer Research.

[10]  M. Waterfield,et al.  Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2 -a]pyridines as novel PI3 kinase p110α inhibitors , 2007 .

[11]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[12]  P. Wipf,et al.  Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. , 2004, Molecular cancer therapeutics.

[13]  P. Frost,et al.  PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors , 2005, Cancer biology & therapy.

[14]  G. Powis,et al.  In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. , 1995, Anticancer research.

[15]  K. Shokat,et al.  A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. , 2007, Cancer research.

[16]  M. Waterfield,et al.  Synthesis and biological evaluation of pyrido[3′,2′:4,5]furo[3,2- d ]pyrimidine derivatives as novel PI3 kinase p110α inhibitors , 2007 .

[17]  T. Ceska,et al.  Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-dihydro-2H-benzo[1,4]oxazines. , 2008, Bioorganic & medicinal chemistry letters.

[18]  H. Bregman,et al.  Ruthenium half-sandwich complexes as protein kinase inhibitors: an N-succinimidyl ester for rapid derivatizations of the cyclopentadienyl moiety. , 2006, Organic letters.

[19]  Tak W. Mak,et al.  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis , 2006, Nature Reviews Cancer.

[20]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[21]  G. Mills,et al.  A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. , 2008, Cancer research.

[22]  Benjamin G. Perry,et al.  Optimization of a series of multi-isoform PI3 kinase inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[23]  L. Toral-Barza,et al.  Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy. , 2008, Journal of medicinal chemistry.

[24]  G. Noronha,et al.  Discovery of 3,3'-(2,4-diaminopteridine-6,7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction. , 2007, Journal of medicinal chemistry.

[25]  P. Hawkins,et al.  Signalling through Class I PI3Ks in mammalian cells. , 2006, Biochemical Society transactions.

[26]  S. Hirono,et al.  Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. , 2006, Journal of the National Cancer Institute.

[27]  Peter J. Alaimo,et al.  Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. , 2004, Bioorganic & medicinal chemistry.

[28]  C. Rommel,et al.  Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma. , 2006, Journal of medicinal chemistry.

[29]  Gary Box,et al.  The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . , 2008, Journal of medicinal chemistry.

[30]  C. Rommel,et al.  PI3Kγ inhibition: towards an 'aspirin of the 21st century'? , 2006, Nature Reviews Drug Discovery.

[31]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[32]  R. Weissleder,et al.  Slow self-activation enhances the potency of viridin prodrugs. , 2008, Journal of medicinal chemistry.

[33]  M. Waterfield,et al.  Synthesis and function of 3-phosphorylated inositol lipids. , 2001, Annual review of biochemistry.

[34]  Roger L. Williams,et al.  Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. , 2000, Molecular cell.

[35]  J. Skotnicki,et al.  Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models. , 2006, Journal of medicinal chemistry.

[36]  Paul Workman,et al.  Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. , 2008, Current opinion in pharmacology.

[37]  Robbie Loewith,et al.  A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling , 2006, Cell.

[38]  J. LoPiccolo,et al.  Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. , 2008, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[39]  G. E. Atilla‐Gokcumen,et al.  Organometallic Compounds with Biological Activity: A Very Selective and Highly Potent Cellular Inhibitor for Glycogen Synthase Kinase 3 , 2006, Chembiochem : a European journal of chemical biology.

[40]  J. Dodge,et al.  Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs. , 1996, Journal of medicinal chemistry.

[41]  Dexin Kong,et al.  ZSTK474 is an ATP‐competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms , 2007, Cancer science.

[42]  L. Pirola,et al.  Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. , 2007, The Biochemical journal.

[43]  P. Wipf,et al.  Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin. , 2004, Organic & biomolecular chemistry.

[44]  Emilio Hirsch,et al.  Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis , 2005, Nature Medicine.

[45]  A. Robertson,et al.  PI 3-kinase p110β: a new target for antithrombotic therapy , 2005, Nature Medicine.

[46]  Brian O Patrick,et al.  Liphagal, a Selective inhibitor of PI3 kinase alpha isolated from the sponge akacoralliphaga: structure elucidation and biomimetic synthesis. , 2006, Organic letters.

[47]  R. Weissleder,et al.  Covalent reactions of wortmannin under physiological conditions. , 2007, Chemistry & biology.