Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216

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

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

DAVIES, S. P., REDDY, H., CAIVANO, M., & COHEN, P. (2000) · Biochemical Journal · doi:10.1042/bj3510095 · Cited by 3,132

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

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

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HSP90 and the chaperoning of cancer

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

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

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

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

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

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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

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

Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., McCormick, F., Tempst, P., et al. (1998) · Science · doi:10.1126/science.279.5351.710 · Cited by 1,059

Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin.

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

Carnero, A., Blanco-Aparicio, C., Renner, O., Link, W., & Leal, J. (2008) · Current Cancer Drug Targets · doi:10.2174/156800908784293659 · Cited by 887

PDK1, the master regulator of AGC kinase signal transduction

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

Serra, V., Markman, B., Scaltriti, M., Eichhorn, P. J. A., Valero, V., Guzman, M., Botero, M. L., Llonch, E., Atzori, F., Di Cosimo, S., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1385 · Cited by 787

PI 3-kinase, Akt and cell survival

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

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

Hsu, A.-L., Ching, T.-T., Wang, D.-S., Song, X., Rangnekar, V. M., & Chen, C.-S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.15.11397 · Cited by 671

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

Basso, A. D., Solit, D. B., Chiosis, G., Giri, B., Tsichlis, P., & Rosen, N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206322200 · Cited by 628

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

Huang, C.-H., Mandelker, D., Schmidt-Kittler, O., Samuels, Y., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Gabelli, S. B., & Amzel, L. M. (2007) · Science · doi:10.1126/science.1150799 · Cited by 560

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

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

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

Yang, J., Cron, P., Good, V. M., Thompson, V., Hemmings, B. A., & Barford, D. (2002) · Nature Structural Biology · doi:10.1038/nsb870 · Cited by 503

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

Lindsley, C. W., Zhao, Z., Leister, W. H., Robinson, R. G., Barnett, S. F., Defeo-Jones, D., Jones, R. E., Hartman, G. D., Huff, J. R., Huber, H. E., et al. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2004.11.011 · Cited by 503

Structural insights into phosphoinositide 3-kinase catalysis and signalling

Walker, E. H., Perisic, O., Ried, C., Stephens, L., & Williams, R. L. (1999) · Nature · doi:10.1038/46319 · Cited by 494

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

Feng, J., Park, J., Cron, P., Hess, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406731200 · Cited by 488

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

Eccles, S. A., Massey, A., Raynaud, F. I., Sharp, S. Y., Box, G., Valenti, M., Patterson, L., de Haven Brandon, A., Gowan, S., Boxall, F., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5256 · Cited by 479

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

Brough, P. A., Aherne, W., Barril, X., Borgognoni, J., Boxall, K., Cansfield, J. E., Cheung, K.-M. J., Collins, I., Davies, N. G. M., Drysdale, M. J., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701018h · Cited by 444

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

Abraham, R. T. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.04.002 · Cited by 440

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

Yang, J., Cron, P., Thompson, V., Good, V. M., Hess, D., Hemmings, B. A., & Barford, D. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00550-6 · Cited by 418

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

Kondapaka, S. B., Singh, S. S., Dasmahapatra, G. P., Sausville, E. A., & Roy, K. (2003) · PubMed · Cited by 407

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

BARNETT, S. F., DEFEO-JONES, D., FU, S., HANCOCK, P. J., HASKELL, K. M., JONES, R. E., KAHANA, J. A., KRAL, A. M., LEANDER, K., LEE, L. L., et al. (2005) · Biochemical Journal · doi:10.1042/bj20041140 · Cited by 396

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

Bozulic, L., Surucu, B., Hynx, D., & Hemmings, B. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.02.024 · Cited by 386

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

Raynaud, F. I., Eccles, S., Clarke, P. A., Hayes, A., Nutley, B., Alix, S., Henley, A., Di-Stefano, F., Ahmad, Z., Guillard, S., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4615 · Cited by 352

Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo

Casamayor, A., MORRICE, N. A., & Alessi, D. R. (1999) · Biochemical Journal · doi:10.1042/0264-6021:3420287 · Cited by 345

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

Modi, S., Stopeck, A. T., Gordon, M. S., Mendelson, D., Solit, D. B., Bagatell, R., Ma, W., Wheler, J., Rosen, N., Norton, L., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.11.7960 · Cited by 335

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

Lawlor, M. A. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf387 · Cited by 319

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

Biondi, R. M., Cheung, P. C. F., Casamayor, A., Deak, M., Currie, R. A., & Alessi, D. R. (2000) · The EMBO Journal · doi:10.1093/emboj/19.5.979 · Cited by 304

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

Arico, S., Pattingre, S., Bauvy, C., Gane, P., Barbat, A., Codogno, P., & Ogier-Denis, E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201119200 · Cited by 303

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

Rhodes, N., Heerding, D. A., Duckett, D. R., Eberwein, D. J., Knick, V. B., Lansing, T. J., McConnell, R. T., Gilmer, T. M., Zhang, S.-Y., Robell, K., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5783 · Cited by 295

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

Garlich, J. R., De, P., Dey, N., Su, J. D., Peng, X., Miller, A., Murali, R., Lu, Y., Mills, G. B., Kundra, V., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-0669 · Cited by 279

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

Solit, D. B., Basso, A. D., Olshen, A. B., Scher, H. I., & Rosen, N. X. (2003) · PubMed · Cited by 277

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

Zhu, J., Huang, J.-W., Tseng, P.-H., Yang, Y.-T., Fowble, J., Shiau, C.-W., Shaw, Y.-J., Kulp, S. K., & Chen, C.-S. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-4063 · Cited by 258

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

Mitsiades, C., Mitsiades, N., & Koutsilieris, M. (2004) · Current Cancer Drug Targets · doi:10.2174/1568009043333032 · Cited by 253

Inhibition of protein kinase B/Akt

Hill, M. M., & Hemmings, B. A. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00193-6 · Cited by 245

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

Luo, Y., Shoemaker, A. R., Liu, X., Woods, K. W., Thomas, S. A., de Jong, R., Han, E. K., Li, T., Stoll, V. S., Powlas, J. A., et al. (2005) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0005 · Cited by 232

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

Sydor, J. R., Normant, E., Pien, C. S., Porter, J. R., Ge, J., Grenier, L., Pak, R. H., Ali, J. A., Dembski, M. S., Hudak, J., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608372103 · Cited by 231

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

Jensen, M. R., Schoepfer, J., Radimerski, T., Massey, A., Guy, C. T., Brueggen, J., Quadt, C., Buckler, A., Cozens, R., Drysdale, M. J., et al. (2008) · Breast Cancer Research · doi:10.1186/bcr1996 · Cited by 229

Hsp90: the vulnerable chaperone

Chiosis, G., Vilenchik, M., Kim, J., & Solit, D. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03245-3 · Cited by 229

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

Feldman, R. I., Wu, J. M., Polokoff, M. A., Kochanny, M. J., Dinter, H., Zhu, D., Biroc, S. L., Alicke, B., Bryant, J., Yuan, S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501367200 · Cited by 228

Deregulation of the Akt Pathway in Human Cancer

Tokunaga, E., Oki, E., Egashira, A., Sadanaga, N., Morita, M., Kakeji, Y., & Maehara, Y. (2008) · Current Cancer Drug Targets · doi:10.2174/156800908783497140 · Cited by 220

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

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

Sato, S., Fujita, N., & Tsuruo, T. (2002) · Oncogene · doi:10.1038/sj.onc.1205225 · Cited by 206

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

Fujita, N., Sato, S., Ishida, A., & Tsuruo, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106736200 · Cited by 198

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

Fan, Q.-W., Cheng, C. K., Nicolaides, T. P., Hackett, C. S., Knight, Z. A., Shokat, K. M., & Weiss, W. A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2154 · Cited by 192

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

Ge, J., Normant, E., Porter, J. R., Ali, J. A., Dembski, M. S., Gao, Y., Georges, A. T., Grenier, L., Pak, R. H., Patterson, J., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm0603116 · Cited by 191

Molecular cloning of a second form of rac protein kinase.

Jones, P. F., Jakubowicz, T., & Hemmings, B. A. (1991) · Cell Regulation · doi:10.1091/mbc.2.12.1001 · Cited by 186

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

Chandarlapaty, S., Sawai, A., Ye, Q., Scott, A., Silinski, M., Huang, K., Fadden, P., Partdrige, J., Hall, S., Steed, P., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1667 · Cited by 186

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

Schnell, C. R., Stauffer, F., Allegrini, P. R., O'Reilly, T., McSheehy, P. M. J., Dartois, C., Stumm, M., Cozens, R., Littlewood-Evans, A., García-Echeverría, C., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1044 · Cited by 174

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

Komander, D., Fairservice, A., Deak, M., Kular, G. S., Prescott, A. R., Peter Downes, C., Safrany, S. T., Alessi, D. R., & van Aalten, D. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600379 · Cited by 170

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

Han, E. K.-H., Leverson, J. D., McGonigal, T., Shah, O. J., Woods, K. W., Hunter, T., Giranda, V. L., & Luo, Y. (2007) · Oncogene · doi:10.1038/sj.onc.1210343 · Cited by 168

Inhibitors of protein kinase C

Gordge, P. C., & Jonathan Ryves, W. (1994) · Cellular Signalling · doi:10.1016/0898-6568(94)90020-5 · Cited by 160

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

Ihle, N. T., Paine-Murrieta, G. D., Berggren, M. I., Baker, A. F., Tate, W. R., Wipf, P., Abraham, R. T., Kirkpatrick, D. L., & Powis, G. (2005) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0149 · Cited by 154

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

Hollingshead, M. G., Alley, M. C., Burger, A. M., Borgel, S. D., Pacula-Cox, C. M., Fiebig, H., & Sausville, E. A. (2005) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-004-0939-2 · Cited by 153

Synthesis and biological activities of novel 17-aminogeldanamycin derivatives

Tian, Z., Liu, Y., Zhang, D., Wang, Z., Dong, S. D., Carreras, C. W., Zhou, Y., Rastelli, G., Santi, D. V., & Myles, D. C. (2004) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2004.07.053 · Cited by 151

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

Zhao, Z., Leister, W., Robinson, R., Barnett, S. F., Defeo-Jones, D., Jones, R. E., Hartman, G. D., Huff, J. R., Huber, H. E., Duggan, M. E., et al. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2004.12.062 · Cited by 146

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

Hill, M. M. C., Andjelković, M., Brazil, D. P., Ferrari, S. M., Fabbro, D., & Hemmings, B. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100174200 · Cited by 139

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

Knight, Z. A., Chiang, G. G., Alaimo, P. J., Kenski, D. M., Ho, C., Coan, K., Abraham, R. T., & Shokat, K. M. (2004) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2004.06.022 · Cited by 137

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

Howes, A. L., Chiang, G. G., Lang, E. S., Ho, C., Powis, G., Vuori, K., & Abraham, R. T. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0698 · Cited by 135

Pharmacodynamic Markers of Perifosine Efficacy

Hennessy, B. T., Lu, Y., Poradosu, E., Yu, Q., Yu, S., Hall, H. S., Carey, M. S., Ravoori, M. K., Gonzalez-Angulo, A. M., Birch, R., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0760 · Cited by 131

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

Janin, Y. L. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050759r · Cited by 127

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

Komander, D., Kular, G. S., Jennifer, B. A. I. N., Elliott, M., Alessi, D. R., & van Aalten, D. M. F. (2003) · Biochemical Journal · doi:10.1042/bj20031119 · Cited by 117

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

Weterings, E., & Chen, D. J. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200705106 · Cited by 116

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

Ernst, D. S., Eisenhauer, E. A., Wainman, N., Davis, M., Lohmann, R. C., Baetz, T. D., Bélanger, K., & Smylie, M. (2005) · Investigational New Drugs · doi:10.1007/s10637-005-1157-4 · Cited by 108

Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents

Neckers, L., & Neckers, K. (2002) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.7.2.277 · Cited by 104

Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors

Breitenlechner, C. B., Wegge, T., Berillon, L., Graul, K., Marzenell, K., Friebe, W.-G., Thomas, U., Schumacher, R., Huber, R., Engh, R. A., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0310479 · Cited by 102

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

Bishop, S., Burlison, J. A., & Blagg, B. S. J. (2007) · Current Cancer Drug Targets · doi:10.2174/156800907780809778 · Cited by 99

A phase II study of perifosine in androgen independent prostate cancer

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

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