Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex

2005 • 5,837 citations

Specificity and mechanism of action of some commonly used protein kinase inhibitors

2000 • 4,109 citations

A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).

1994 • 3,249 citations

Specificity and mechanism of action of some commonly used protein kinase inhibitors

2000 • 3,002 citations

Mechanism of activation of protein kinase B by insulin and IGF-1.

1996 • 2,965 citations

Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα

1997 • 2,747 citations

HSP90 and the chaperoning of cancer

2005 • 2,352 citations

Crystal Structure of an Hsp90–Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent

1997 • 1,345 citations

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

2007 • 1,234 citations

Dual Role of Phosphatidylinositol-3,4,5-trisphosphate in the Activation of Protein Kinase B

1997 • 1,190 citations

Structural Determinants of Phosphoinositide 3-Kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine

2000 • 1,121 citations

A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling

2006 • 1,119 citations

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 • 1,099 citations

Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Activation of Protein Kinase B

1998 • 1,050 citations

Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin

1999 • 979 citations

PDK1, the master regulator of AGC kinase signal transduction

2004 • 785 citations

The PTEN/PI3K/AKT Signalling Pathway in Cancer, Therapeutic Implications

2008 • 783 citations

PI 3-kinase, Akt and cell survival

2004 • 767 citations

NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations

2008 • 757 citations

Wortmannin Inactivates Phosphoinositide 3-Kinase by Covalent Modification of Lys-802, a Residue Involved in the Phosphate Transfer Reaction

1996 • 673 citations

The Cyclooxygenase-2 Inhibitor Celecoxib Induces Apoptosis by Blocking Akt Activation in Human Prostate Cancer Cells Independently of Bcl-2

2000 • 670 citations

Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function

2002 • 610 citations

Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily.

1991 • 537 citations

Akt activation by growth factors is a multiple-step process: the role of the PH domain

1998 • 531 citations

The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations

2007 • 523 citations

Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors

2004 • 494 citations

Crystal structure of an activated Akt/Protein Kinase B ternary complex with GSK3-peptide and AMP-PNP

2002 • 492 citations

Identification of a PKB/Akt Hydrophobic Motif Ser-473 Kinase as DNA-dependent Protein Kinase

2004 • 485 citations

Structural insights into phosphoinositide 3-kinase catalysis and signalling

1999 • 478 citations

NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

2008 • 461 citations

PI 3-kinase related kinases: ‘big’ players in stress-induced signaling pathways

2004 • 433 citations

4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

2007 • 424 citations

Molecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation

2002 • 416 citations

Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors

2005 • 400 citations

Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.

2003 • 399 citations

PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival

2008 • 387 citations

Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases

2007 • 354 citations

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 • 334 citations

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 • 326 citations

Essential role of PDK1 in regulating cell size and development in mice

2002 • 322 citations

Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA

2000 • 297 citations

Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line

2002 • 297 citations

Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

2008 • 285 citations

Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol.

2003 • 275 citations

A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity

2008 • 273 citations

From the Cyclooxygenase-2 Inhibitor Celecoxib to a Novel Class of 3-Phosphoinositide-Dependent Protein Kinase-1 Inhibitors

2004 • 258 citations

The Akt Pathway: Molecular Targets for Anti-Cancer Drug Development

2004 • 250 citations

Inhibition of protein kinase B/Akt

2002 • 241 citations

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

2006 • 228 citations

Hsp90: the vulnerable chaperone

2004 • 228 citations

Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo

2005 • 219 citations

Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity

1992 • 217 citations

Deregulation of the Akt Pathway in Human Cancer

2008 • 215 citations

NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

2008 • 212 citations

Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine)

2002 • 210 citations

Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase–Akt/PKB survival pathway

2003 • 207 citations

Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1

2005 • 207 citations

Involvement of Hsp90 in Signaling and Stability of 3-Phosphoinositide-dependent Kinase-1

2002 • 194 citations

A Dual Phosphoinositide-3-Kinase α/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma

2007 • 190 citations

Design, Synthesis, and Biological Evaluation of Hydroquinone Derivatives of 17-Amino-17-demethoxygeldanamycin as Potent, Water-Soluble Inhibitors of Hsp90

2006 • 184 citations

Molecular cloning of a second form of rac protein kinase.

1991 • 182 citations

SNX2112, a Synthetic Heat Shock Protein 90 Inhibitor, Has Potent Antitumor Activity against HER Kinase–Dependent Cancers

2008 • 178 citations

Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates

2004 • 175 citations

Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging

2008 • 174 citations

Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition

2007 • 161 citations

Inhibitors of protein kinase C

1994 • 160 citations

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 • 149 citations

Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

2004 • 149 citations

In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative

2005 • 147 citations

Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors

2005 • 144 citations

Insulin-stimulated Protein Kinase B Phosphorylation on Ser-473 Is Independent of Its Activity and Occurs through a Staurosporine-insensitive Kinase

2001 • 143 citations

The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures

2007 • 135 citations

Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold

2004 • 134 citations

Pharmacodynamic Markers of Perifosine Efficacy

2007 • 130 citations

Heat Shock Protein 90 Inhibitors. A Text Book Example of Medicinal Chemistry?

2005 • 125 citations

DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys?

2007 • 112 citations

Wortmannin, an antibiotic produced by Penicillium wortmanni

1957 • 112 citations

Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition

2003 • 112 citations

Phase II Study of Perifosine in Previously Untreated Patients with Metastatic Melanoma

2005 • 108 citations

Targeting Serine / Threonine Protein Kinase B / Akt and Cell-cycle Checkpoint Kinases for Treating Cancer

2002 • 105 citations

Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents

2002 • 101 citations

Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors

2004 • 100 citations

Hsp90: A Novel Target for the Disruption of Multiple Signaling Cascades

2007 • 99 citations

A phase II study of perifosine in androgen independent prostate cancer

2005 • 98 citations

Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers

2007 • 87 citations

Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma

2008 • 86 citations

Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways

2003 • 85 citations

Inverse In Silico Screening for Identification of Kinase Inhibitor Targets

2007 • 84 citations

A Structural Comparison of Inhibitor Binding to PKB, PKA and PKA-PKB Chimera

2007 • 84 citations

UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: A study of the Princess Margaret Hospital Phase II consortium

2007 • 72 citations

Structure-Based design of 2-Arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-Dependent kinases 1 and 2

2003 • 69 citations

PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors

2005 • 66 citations

In vitro Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines

2004 • 65 citations

Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma

2008 • 64 citations

Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment

2008 • 62 citations

Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery

2008 • 60 citations

Design and Crystal Structures of Protein Kinase B-Selective Inhibitors in Complex with Protein Kinase A and Mutants

2004 • 57 citations

Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines

2007 • 57 citations

7-Hydroxystaurosporine (UCN-01) Inhibition of Akt Thr308 but not Ser473 Phosphorylation

2004 • 57 citations

Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells

2005 • 56 citations

Regulation of class III (Vps34) PI3Ks

2007 • 55 citations

Mutants of Protein Kinase A that Mimic the ATP-binding Site of Protein Kinase B (AKT)

2003 • 50 citations

Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity

2007 • 50 citations

Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: Design, synthesis and biological activity

2007 • 45 citations

Inhibitors of HSP90 and other chaperones for the treatment of cancer

2004 • 45 citations

Epidemiology and clinical burden of acute myeloid leukemia

2003 • 45 citations

Optimal Classes of Chemotherapeutic Agents Sensitized by Specific Small-Molecule Inhibitors of Akt In Vitro and In Vivo

2005 • 41 citations

Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: Optimization of BX-517

2007 • 39 citations

Expression, purification, characterization and homology modeling of active Akt/PKB, a key enzyme involved in cell survival signaling

2001 • 35 citations

Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors

2007 • 27 citations

Survival-signaling pathway as a promising target for cancer chemotherapy

2003 • 24 citations

Targeting aberrant PI3K pathway signaling with XL147, a potent, selective and orally bioavailable PI3K inhibitor

2007 • 15 citations

XL765 targets tumor growth, survival, and angiogenesis in preclinical models by dual inhibition of PI3K and mTOR

2007 • 14 citations

Potentiating the antitumor effects of chemotherapy with the selective PI3K inhibitor XL147

2007 • 13 citations

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 • 8 citations

BIIB021 is a small molecule inhibitor of the heat shock protein, Hsp90, that shows potent anti-tumor activity in preclinical models

2007 • 3 citations

Perifosine

2000 • 3 citations

Deleted Work

1955 • 0 citations