Drug discovery approaches targeting the PI3K/Akt pathway in cancer

[1]  J. Baselga,et al.  NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. , 2008, Cancer research.

[2]  C. Schnell,et al.  Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. , 2008, Cancer research.

[3]  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.

[4]  H. Einsele,et al.  Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma , 2008, Leukemia.

[5]  Wolfgang Link,et al.  The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. , 2008, Current cancer drug targets.

[6]  B. Hemmings,et al.  PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. , 2008, Molecular cell.

[7]  Joseph Schoepfer,et al.  NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models , 2008, Breast Cancer Research.

[8]  L. Pearl,et al.  NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. , 2008, Cancer research.

[9]  Robert A Copeland,et al.  Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. , 2008, Cancer research.

[10]  K. Shokat,et al.  Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma , 2008, Molecular Cancer Therapeutics.

[11]  A. Kral,et al.  Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[12]  N. Munshi,et al.  Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment , 2008, Clinical Cancer Research.

[13]  Yoshihiro Kakeji,et al.  Deregulation of the Akt pathway in human cancer. , 2008, Current cancer drug targets.

[14]  C. García-echeverría,et al.  Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery , 2008, Expert opinion on therapeutic targets.

[15]  Sarat Chandarlapaty,et al.  SNX2112, a Synthetic Heat Shock Protein 90 Inhibitor, Has Potent Antitumor Activity against HER Kinase–Dependent Cancers , 2008, Clinical Cancer Research.

[16]  Yiling Lu,et al.  Pharmacodynamic Markers of Perifosine Efficacy , 2007, Clinical Cancer Research.

[17]  Bert Vogelstein,et al.  The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations , 2007, Science.

[18]  C. Hudis,et al.  Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  L. Meijer,et al.  Inverse in silico screening for identification of kinase inhibitor targets. , 2007, Chemistry & biology.

[20]  Mike Wood,et al.  4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. , 2007, Journal of medicinal chemistry.

[21]  R. Abraham,et al.  Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines , 2007, Molecular Cancer Therapeutics.

[22]  A. Laird XL765 targets tumor growth, survival, and angiogenesis in preclinical models by dual inhibition of PI3K and mTOR , 2007 .

[23]  G. Shapiro,et al.  Targeting aberrant PI3K pathway signaling with XL147, a potent, selective and orally bioavailable PI3K inhibitor , 2007 .

[24]  S. Kasibhatla,et al.  BIIB021 is a small molecule inhibitor of the heat shock protein, Hsp90, that shows potent anti-tumor activity in preclinical models , 2007 .

[25]  P. Foster Potentiating the antitumor effects of chemotherapy with the selective PI3K inhibitor XL147 , 2007 .

[26]  P. LoRusso,et al.  Biomarker development for XL765, a potent and selective oral dual inhibitor of PI3K and mTOR currently being administered to patients in a Phase I clinical trial , 2007 .

[27]  David J. Chen,et al.  DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys? , 2007, The Journal of cell biology.

[28]  Kristiina Vuori,et al.  The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures , 2007, Molecular Cancer Therapeutics.

[29]  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.

[30]  T. Hunter,et al.  Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition , 2007, Oncogene.

[31]  G. Pond,et al.  UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. , 2007, Gynecologic oncology.

[32]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[33]  M. Adler,et al.  Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: optimization of BX-517. , 2007, Bioorganic & medicinal chemistry letters.

[34]  M. Adler,et al.  Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity. , 2007, Bioorganic & medicinal chemistry letters.

[35]  M. Waterfield,et al.  Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. , 2007, Cancer research.

[36]  B. Blagg,et al.  Hsp90: a novel target for the disruption of multiple signaling cascades. , 2007, Current cancer drug targets.

[37]  J. Backer,et al.  Regulation of class III (Vps34) PI3Ks. , 2007, Biochemical Society transactions.

[38]  Ian Collins,et al.  A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. , 2007, Journal of molecular biology.

[39]  S. Ramalingam,et al.  Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers , 2007, Clinical Cancer Research.

[40]  Jie Ge,et al.  Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90 , 2006, Proceedings of the National Academy of Sciences.

[41]  James R. Porter,et al.  Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. , 2006, Journal of medicinal chemistry.

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

[43]  Y. Janin Heat Shock Protein 90 Inhibitors. A Text Book Example of Medicinal Chemistry , 2006 .

[44]  Yiling Lu,et al.  Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells , 2006, Oncogene.

[45]  K. Bélanger,et al.  Phase II Study of Perifosine in Previously Untreated Patients with Metastatic Melanoma , 2005, Investigational New Drugs.

[46]  J. Fisher,et al.  Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. , 2005, Neoplasia.

[47]  S. Steinberg,et al.  A phase II study of perifosine in androgen independent prostate cancer , 2005, Cancer biology & therapy.

[48]  S. Lindquist,et al.  HSP90 and the chaperoning of cancer , 2005, Nature Reviews Cancer.

[49]  R. Huber,et al.  Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants. , 2005, Journal of medicinal chemistry.

[50]  P. Wipf,et al.  The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non–small cell lung cancer xenografts , 2005, Molecular Cancer Therapeutics.

[51]  Yan Shi,et al.  Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo , 2005, Molecular Cancer Therapeutics.

[52]  Marc Adler,et al.  Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1* , 2005, Journal of Biological Chemistry.

[53]  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.

[54]  E. Sausville,et al.  In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative , 2005, Cancer Chemotherapy and Pharmacology.

[55]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[56]  Zhijian Zhao,et al.  Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[57]  Zhijian Zhao,et al.  Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[58]  E. Sausville,et al.  7-Hydroxystaurosporine (UCN-01) Inhibition of Akt Thr308 but not Ser473 Phosphorylation , 2004, Clinical Cancer Research.

[59]  D. Solit,et al.  Hsp90: the vulnerable chaperone. , 2004, Drug discovery today.

[60]  Yaoquan Liu,et al.  Synthesis and biological activities of novel 17-aminogeldanamycin derivatives. , 2004, Bioorganic & medicinal chemistry.

[61]  A. Prescott,et al.  Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates , 2004 .

[62]  B. Hemmings,et al.  Identification of a PKB/Akt Hydrophobic Motif Ser-473 Kinase as DNA-dependent Protein Kinase*♦ , 2004, Journal of Biological Chemistry.

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

[64]  Robert T Abraham,et al.  PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. , 2004, DNA repair.

[65]  E. Sausville,et al.  In vitro Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines , 2004, Clinical Cancer Research.

[66]  S. Kulp,et al.  From the Cyclooxygenase-2 Inhibitor Celecoxib to a Novel Class of 3-Phosphoinositide-Dependent Protein Kinase-1 Inhibitors , 2004, Cancer Research.

[67]  M. Drysdale,et al.  Inhibitors of HSP90 and other chaperones for the treatment of cancer , 2004 .

[68]  Michael Koutsilieris,et al.  The Akt pathway: molecular targets for anti-cancer drug development. , 2004, Current cancer drug targets.

[69]  J. Downward PI 3-kinase, Akt and cell survival. , 2004, Seminars in cell & developmental biology.

[70]  D. V. van Aalten,et al.  PDK1, the master regulator of AGC kinase signal transduction. , 2004, Seminars in cell & developmental biology.

[71]  R. Huber,et al.  Structure-based optimization of novel azepane derivatives as PKB inhibitors. , 2004, Journal of medicinal chemistry.

[72]  R. Griffin Structure-Based Design of 2 -Arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine Inhibitors of Cyclin-Dependent Kinases 1 and 2. , 2003 .

[73]  E. Sausville,et al.  Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. , 2003, Molecular cancer therapeutics.

[74]  David Komander,et al.  Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition. , 2003, The Biochemical journal.

[75]  C. Pashos,et al.  Epidemiology and clinical burden of acute myeloid leukemia , 2003, Expert review of anticancer therapy.

[76]  M. Noble,et al.  Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2. , 2003, Bioorganic & medicinal chemistry letters.

[77]  E. Sausville,et al.  Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. , 2003, Blood.

[78]  R. Huber,et al.  Mutants of protein kinase A that mimic the ATP-binding site of protein kinase B (AKT). , 2003, Journal of molecular biology.

[79]  Takashi Tsuruo,et al.  Survival-signaling pathway as a promising target for cancer chemotherapy , 2003, Cancer Chemotherapy and Pharmacology.

[80]  A. Olshen,et al.  Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. , 2003, Cancer research.

[81]  H. Bartelink,et al.  Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase–Akt/PKB survival pathway , 2003, Anti-cancer drugs.

[82]  Brian A. Hemmings,et al.  Crystal structure of an activated Akt/Protein Kinase B ternary complex with GSK3-peptide and AMP-PNP , 2002, Nature Structural Biology.

[83]  N. Rosen,et al.  Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function* , 2002, The Journal of Biological Chemistry.

[84]  L. Neckers,et al.  Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents , 2002, Expert opinion on emerging drugs.

[85]  Qun Li,et al.  Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. , 2002, Current topics in medicinal chemistry.

[86]  S. Arico,et al.  Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line* , 2002, The Journal of Biological Chemistry.

[87]  A. Prescott,et al.  Essential role of PDK1 in regulating cell size and development in mice , 2002, The EMBO journal.

[88]  D. Barford,et al.  Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. , 2002, Molecular cell.

[89]  A. Ishida,et al.  Involvement of Hsp90 in Signaling and Stability of 3-Phosphoinositide-dependent Kinase-1* , 2002, The Journal of Biological Chemistry.

[90]  T. Tsuruo,et al.  Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine) , 2002, Oncogene.

[91]  B. Hemmings,et al.  Inhibition of protein kinase B/Akt. implications for cancer therapy. , 2002, Pharmacology & therapeutics.

[92]  M. Andjelkovic,et al.  Insulin-stimulated Protein Kinase B Phosphorylation on Ser-473 Is Independent of Its Activity and Occurs through a Staurosporine-insensitive Kinase* , 2001, The Journal of Biological Chemistry.

[93]  C. Kumar,et al.  Expression, purification, characterization and homology modeling of active Akt/PKB, a key enzyme involved in cell survival signaling. , 2001, Biochimica et biophysica acta.

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

[95]  A. Hsu,et al.  The Cyclooxygenase-2 Inhibitor Celecoxib Induces Apoptosis by Blocking Akt Activation in Human Prostate Cancer Cells Independently of Bcl-2* , 2000, The Journal of Biological Chemistry.

[96]  Maria Deak,et al.  Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C‐terminal residues of PKA , 2000, The EMBO journal.

[97]  Christian Ried,et al.  Structural insights into phosphoinositide 3-kinase catalysis and signalling , 1999, Nature.

[98]  D R Alessi,et al.  Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. , 1999, The Biochemical journal.

[99]  L. Pearl,et al.  Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. , 1999, Journal of medicinal chemistry.

[100]  Frank McCormick,et al.  Akt activation by growth factors is a multiple-step process: the role of the PH domain , 1998, Oncogene.

[101]  F. McCormick,et al.  Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. , 1998, Science.

[102]  F. McCormick,et al.  Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. , 1997, Science.

[103]  Neal Rosen,et al.  Crystal Structure of an Hsp90–Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent , 1997, Cell.

[104]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

[105]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[106]  M. Zvelebil,et al.  Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction , 1996, Molecular and cellular biology.

[107]  W. Ryves,et al.  Inhibitors of protein kinase C. , 1994, Cellular signalling.

[108]  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.

[109]  P. Davis,et al.  Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity. , 1992, Journal of medicinal chemistry.

[110]  B. Hemmings,et al.  Molecular cloning of a second form of rac protein kinase. , 1991, Cell regulation.

[111]  B. Hemmings,et al.  Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

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

[113]  C. Lindsley,et al.  Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity. , 2008, Bioorganic & medicinal chemistry letters.

[114]  Bert Vogelstein,et al.  The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. , 2007, Science.

[115]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[116]  A. Voss,et al.  CURRENT DEVELOPMENT STATUS OF THE SECOND GENERATION ALKYLPHOSPHOCHOLINE ANALOG PERIFOSINE , 1998 .

[117]  M. Bibby,et al.  MORPHOLOGICAL CHANGES AND CYTOKINE GENE EXPRESSION IN TUMOR XENOGRAFTS FOLLOWING TREATMENT WITH THE ALKYLPHOSPHOCHOLINES HEXADECYLPHOSPHOCHOLINE AND P ERIFOSINE , 1998 .

[118]  P. W. Brian,et al.  Wortmannin, an antibiotic produced by Penicillium wortmanni , 1957 .

[119]  A. Kral,et al.  Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors , 2022 .