The PI3K/Akt pathway: Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors

Current Cancer Drug Targets

Volumn 8, Issue 1, 2008, Pages 7-18

  Lindsley, Craig W ^a,b   Barnett, Stanley F ^c   Layton, Mark E ^d   Bilodeau, Mark T ^d  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b VANDERBILT UNIVERSITY   (United States)

^c Department of Cancer Research ^*  (United States)

^d MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Akt; Allosteric; Apoptosis; Cancer; Chemotherapy; Inhibitors; Kinase; PKB

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; ADENOSINE TRIPHOSPHATE; CAMPTOTHECIN; COMPOUND 19; DOXORUBICIN; IMATINIB; ISOENZYME; N (5 BENZAMIDO 4 OXO 6 PHENYLHEXANOYL)PROLINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; PROTEIN KINASE INHIBITOR; PURVALANOL; RAPAMYCIN; SR 13668; STAUROSPORINE; TRASTUZUMAB; UNCLASSIFIED DRUG;

ALLOSTERISM; APOPTOSIS; CANCER THERAPY; ENZYME ACTIVATION; NONHUMAN; REVIEW; TISSUE DISTRIBUTION;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ADENOSINE TRIPHOSPHATE; ALLOSTERIC REGULATION; ANIMALS; ENZYME INHIBITORS; HUMANS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TECHNOLOGY, PHARMACEUTICAL;

EID: 39049171769     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800908783497096     Document Type: Review

References (128)

1. Kumar, C.; Madison, V. AKT crystal structure and AKT-specific inhibitors. Oncogene 2005, 24(50), 7493-7501.
2. Cheng, J. Q.; Lindsley, C. W.; Cheng, G. Z.; Yang, H.; Nicosia, S. V. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 2005, 24(50), 7482-7492.
3. Yoeli-Lerner, M.; Toker, A. Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell Cycle 2006, 5(6), 603-605.
4. Chen, Y. L.; Law, P. -Y; Loh, H. H. Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy. Curr. Med. Chem. Anticancer Agents 2005, 5(6), 575-589.
5. Altomare, D. A.; Testa, J. R. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005, 24(50), 7455-7464.
6. Lu, Y.; Wang, H.; Mills, G. B. Targeting PI3K-AKT pathway for cancer therapy. Rev. Clin. Exp. Hematol. 2003, 7, 205-228.
7. Zdychova, J.; Komers, R. Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications. Physiol. Res. 2005, 54(1), 1-16.
8. Mitsiades, C. S.; Mitsiades, N.; Koutsilieris, M.; Nicholson, K. M.; Anderson, N. G.; Neri, L. M.; Borgatti, P.; Capitani, S.; Martelli, M.; Brazil, D. P.; Hemmings, B. A. The Akt pathway: molecular targets for anti-cancer drug development. Curr. Cancer Drug Targets 2004, 4, 235-256.
9. Luo, J.; Manning, B. D.; Cantley, L. C. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003, 4, 257-262.
10. Farese, R. V.; Sajan, M. P.; Standaert, M. L. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp. Biol. Med. (Maywood) 2005, 230(9), 593-605.
11. Garofalo, R. S.; Orena, S. J.; Rafidi, K.; Torchia, A. J.; Stock, J. L.; Hildebrandt, A. L.; Coskran, T.; Black, S. C.; Brees, D. J.; Wicks, J. R.; McNeish, J. D.; Coleman, K. G. Severe diabetes, agedependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J. Clin. Invest. 2003, 112, 197-208.
12. Cho, H.; Mu, J.; Kim, J. K.; Thorvaldsen, J. L.; Chu, Q. W.; Crenshaw, E. B.; Kaestner, K. H.; Bartolomei, M. S.; Shulman, G. I.; Birnbaum, M. J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001, 292, 1728-1731.
13. Samuels, Y.; Ericson, K. Oncogenic PI3K and its role in cancer. Curr. Opin. Oncol. 2006, 18(1), 77-82.
14. Wetzker, R.; Rommel, C. Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr. Pharm. Des. 2004, 10(16), 1915-1922.
15. Chen, K. Q.; Iribarren, P.; Gong, W. H.; Wang, J. M. The Essential Role of Phosphoinositide 3-Kinases (PI3Ks) in Regulating Pro-Inflammatory Responses and the Progression of Cancer. Cell Mol. Immunol. 2005, 2(4), 241-252.
16. Simpson, L.; Parsons, R. PTEN: Life as a tumor suppressor. Exp. Cell Res. 2001, 264, 29-41.
17. Chow, L. M.; Baker, S. J. PTEN function in normal and neoplastic growth. Cancer Lett. 2006, 241(2), 184-196.
18. Hede, K. PTEN takes center stage in cancer stem cell research, works as tumor suppressor. J. Natl. Cancer Inst. 2006, 98(12), 808-809.
19. Cully, M.; You, H.; Levine, A. J.; Mak, T. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer 2006, 6(3), 184-192.
20. Sulis, M. L.; Parsons, R. PTEN: from pathology to biology. Trends Cell Biol. 2003, 13, 478-483.
21. Scheper, M. A.; Nikitakis, N. G.; Sarlani, E.; Sauk, J. J.; Meiller, T. F. Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2006, 101(5), 625-631.
22. Derrey, S.; Proust, F.; Debono, B.; Langlois, O.; Layet, A.; Layet, V.; Longy, M.; Freger, P.; Laquerriere, A. Association between Cowden syndrome and Lhermitte-Duclos disease: report of two cases and review of the literature. Surg. Neurol. 2004, 61, 447-454.
23. Pilarski, R.; Eng, C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J. Med. Genet. 2004, 41, 323-326.
24. Hendriks, Y. M.; Verhallen, J. T.; van-der-Smagt, J. J.; Kant, S. G.; Hilhorst, Y.; Hoefsloot, L.; Hansson, K. B.; van-der-Straaten, P. J.; Boutkan, H.; Breuning, M. H.; Vasen, H. F.; Brocker-Vriends, A. H. Bannayan-Riley- Ruvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation-positive cases. Fam. Cancer 2003, 2, 79-85.
25. Zhou, X. P.; Marsh, D. J.; Morrison, C. D.; Chaudhury, A. R.; Maxwell, M.; Reifenberger, G.; Eng, C. Germline Inactivation of PTEN and Dysregulation of the Phosphoinositol-3-Kinase/Akt Pathway Cause Human Lhermitte-Duclos Disease in Adults. Am. J. Hum. Genet. 2003, 73, 1191-1198.
26. Chang, F.; Lee, J. T.; Navolanic, P. M.; Steelman, L. S.; Shelton, J.G.; Blalock, W. L.; Franklin, R. A.; McCubrey, J. A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003, 17, 590-603.
27. Fresno-Vara, J. A.; Casado, E.; de-Castro, J.; Cejas, P.; Belda-Iniesta, C.; Gonzalez-Baron, M. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev. 2004, 30, 193-204.
28. Le Page, C.; Koumakpayi, I. H.; Alam-Fahmy, M.; Mes-Masson, A. -M.; Saad, F. Expression and localization of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. Br. J. Cancer 2006, 94(12), 1906-1912.
29. Paweletz, C. P.; Charboneau, L.; Bichsel, V. E.; Simone, N. L.; Chen, T.; Gillespie, J. W.; Emmert Buck, M. R.; Roth, M. J.; Petricoin, E. F.; Liotta, L. A Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 2001, 20, 1981-1989.
30. Malik, S. N.; Brattain, M.; Ghosh, P. M.; Troyer, D. A.; Prihoda, T.; Bedolla, R.; Kreisberg, J. I. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin. Cancer Res. 2002, 8(4), 1168-1171.
31. Xin, L.; Teitell, M. A.; Lawson, D. A.; Kwon, A.; Mellinghoff, I. K.; Witte, O. N. Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc. Natl. Acad. Sci. USA 2006, 103(20), 7789-7794.
32. Page, C. L.; Koumakpayi, I.; Alam-Fahmy, M.; Mes-Masson, A. -M.; Saad, F. Expression and localization of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. Br. J. Cancer 2006, 94, 1906-1912.
33. Shi, W.; Zhang, X.; Pintilie, M.; Ma, N.; Miller, N.; Banerjee, D.; Tsao, M. S.; Mak, T.; Fyles, A.; Liu, F. F. Dysregulated PTENPKB and negative receptor status in human breast cancer. Int. J. Cancer 2003, 104, 195-203.
34. Kirkegaard, T.; Witton, C. J.; McGlynn, L. M.; Tovey, S. M.; Dunne, B.; Lyon, A.; Bartlett, J. M. Akt activation predicts outcome in breast cancer patients treated with tamoxifen. J. Pathology 2006, 207(2), 139-146.
35. Itoh, N.; Semba, S.; Ito, M.; Takeda, H.; Kawata, S.; Yamakawa, M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 2002, 94(12), 3127-3134.
36. Roy, H. K.; Olusola, B. F.; Clemens, D. L.; Karolski, W. J.; Ratashak, A.; Lynch, H. T.; Smyrk, T. C. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 2002, 23(1), 201-205.
37. Bayascas, J. R.; Leslie, N. R.; Parsons, R.; Fleming, S.; Alessie, D. R. Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/- mice. Curr. Biol. 2005, 15, 1839-1846.
38. Chen, M. -L.; Xu, P. -Z.; Peng, X. -D.; Chen, W. S.; Guzman, G.; Yang, X.; Di Cristofano, A.; Pandolfi, P. P.; Hay, N. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes and Development 2006, 20, 1569-1574.
39. Deininger, M.; Buchdunger, E.; Druker, B. J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005, 105(7), 2640-2653.
40. Steinert, D. M.; McAuliffe, J. C.; Trent, J. C. Imatinib mesylate in the treatment of gastrointestinal stromal tumour. Expert Opin. Pharmacother. 2005, 6(1), 105-113.
41. Cappuzzo, F.; Finocchiaro, G.; Metro, G.; Bartolini, S.; Magrini, E.; Cancellieri, A.; Trisolini, R.; Castaldini, L.; Tallini, G.; Crino, L. Clinical experience with gefitinib:an update. Crit. Rev. Oncology/hematology 2006, 58, 31-45.
42. Tang, P. A.; Tsao, M. -S.; Moore, M. J. A review of erlotinib and its clinical use. Expert Opin. Pharmacother. 2006, 7(2), 177-193.
43. Plosker, G. L.; Keam, S. J. Trastuzumab: A review of its use in the management of Her2-positive metastatic and early-stage breast cancer. Drugs 2006, 66(4), 449-475.
44. Cappuzzo, F.; Marrini, E.; Ceresoli, G. L. Bartolini, S.; Rossi, E.; Ludovini, V.; Gregorc, V.; Ligorio, C.; Cancellieri, A.; Damiani, S.; Spreafico, A.; Paties, C. T.; Lombardo, L.; Calandri, C.; Bellezza, G.; Tonato, M.; Crino, L. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small cell lung cancer. J. Natl. Cancer Inst. 2004, 96, 113-1141.
45. Cappuzzo, F.; Hirsch, F. R.; Rossi, E.; Bartolini, S.; GiCeresoli, G. L.; Bemis, L.; Haney, J.; Witta, S.; Danenberg, K.; Domenichini, I.; Ludovini, V.; Magrini, E.; Gregorc, V.; Doglioni, C.; Sidoni, A.; Tonato, M.; Franklin, W. A.; Crino, L.; Bunn, Jr., P. A.; Varella-Garcia, M. Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non-Small-Cell Lung Cancer. J. Nat. Cancer Inst. 2005, 97(9), 643-655.
46. Longva, K. E.; Pedersen, N. M.; Haslekas, C.; Stang, E.; Madshus, I. H. Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. Int. J. Cancer 2005, 116, 359-367.
47. Fujita, T.; Doihara, H.; Kawasaki, K.; Takabatake, H.; Washio, K.; Ogasawara, Y.; Shimizu, N. Pten activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br. J. Cancer 2006, 94, 247-252.
48. Haas-Kogan, D. A.; Prados, M. D.; Tihan, T.; Eberhard, D. A.; Jelluma, N.; Arvold, N. D.; Baumber, R.; Lamborn, K. R.; Kapadia, A.; Malec, M.; Berger, M. S.; Stokoe, D. Epidermal Growth Factor Receptor, Protein Kinase B/Akt, and Glioma Response to Erlotinib. J. Natl. Cancer Inst. 2005, 97(12), 880-887.
49. Buck, E.; Eyzaguirre, A.; Haley, J. D.; Gibson, N. W.; Cagnoni, P.; Iwata, K. K. Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity. Mol. Cancer Ther. 2006, 5(8), 2051-2059.
50. Burchert, A.; Wang, Y.; Cai, D.; von Bubnoff, N.; Paschka, P.; Müller-Brüsselbach, S.; Ottmann, O G.; Duyster, J.; Hochhaus, A.; Neubauer, A. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 2005, 19, 1774-1782.
51. Tarn, C.; Skorobogatko, Y. V.; Taguchi, T.; Eisenberg, B.; von Mehren, M.; Godwin, A. K. Therapeutic Effect of Imatinib in Gastrointestinal Stromal Tumors: AKT Signaling Dependent and Independent Mechanisms. Cancer Res. 2006, 6(10), 5477-5486.
52. Suzuki, A.; de la Pompa, J. L.; Stambolic, V. A; Elia, J.; Sasaki, T.; del Barco Barrantes, I.; Ho, A.; Wakeham, A.; Itie, A.; Khoo, W.; Mak, T. W. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 1998, 8, 1169-1178.
53. Di Cristofano, A.; Pesce, B.; Cordon-Cardo, C.; Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression, Nat. Genet. 1998, 19, 348-355.
54. Podsypanina, K.; Ellenson, L. H.; Nemes, A.; Gu, J.; Tamura, M.; Yamada, K. M.; Cordon-Cardo, C.; Catoretti, G.; Fisher, P. E.; Parsons, R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems, Proc. Natl. Acad. Sci. USA 1999, 96, 1563-1568.
55. Bayascas, J.; Leslie, N.; Parsons, R.; Fleming, S.; Alessi, D. Hypomorphic Mutation of PDK1 Suppresses Tumorigenesis in PTEN Mice. Curr. Biology 2005, 15(20), 1839-1846.
56. Chen, M. -L.; Xu, P. -Z.; Peng, X.; Chen, W. S.; Guzman, G.; Yang, X.; Di Cristofano, A.; Pandolfi, P. P.; Hay, N. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes & Dev. 2006, 20, 1569-1574.
57. 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.; Malinowski, J.; McAvoy, E. M.; Nahas, D. D.; Robinson, R.; Huber, H. E. Identification and Characterization of Pleckstrin Homology Domain Dependent and Isozyme Specific Akt Inhibitors. Biochemical J. 2004, 385, 399-408.
58. Lindsley, C. W.; Zhao, Z.; Duggan, M. E.; Barnett, S. F.; Defeo-Jones, D.; Huber, H. E.; Huff, J. R.; Hartman, G. D.; Leister, W.; Kral, A.; Fu, S.; Hancock, P. J.; Haskell, K. A.; Jones, R. E.; Robinson, R. Allosteric Akt (PKB) Kinase Inhibitors. Discovery and SAR of Isozyme Selective Inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 761-764.
59. Laine, J.; Kunstle, G.; Obata, T.; Noguchi, M. Differential regulation of Akt kinase isoforms by the members of TCL1 oncogene family. J. Biol. Chem. 2002, 277, 3743-3751.
60. Cho, H.; Thorvaldsen, J. L.; Chu, Q. W.; Feng, F.; Birnbaum, M. J. Akt1/PKB alpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 2001, 276, 38349-38352.
61. Garofalo, R. S.; Orena, S. J.; Rafidi, K.; Torchia, A. J.; Stock, J. L.; Hildebrandt, A. L.; Coskran, T.; Black, S. C.; Brees, D. J.; Wicks, J. R.; McNeish, J. D.; Coleman, K. G. Severe diabetes, age dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J. Clin. Invest. 2003, 112, 197-208.
62. Cho, H.; Mu, J.; Kim, J. K.; Thorvaldsen, J. L.; Chu, Q. W.; Crenshaw, E. B.; Kaestner, K. H.; Bartolomei, M. S.; Shulman, G. I.; Birnbaum, M. J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001, 292, 1728-1731.
63. Easton, R. M.; Cho, H.; Roovers, K.; Shineman, D. W.; Mizrahi, M.; Forman, M. S.; Lee, V. M. -Y.; Szabolcs, M.; de Jong, R.; Oltersdorf, T.; Ludwig, T.; Efstratiadis, A.; Birnbaum, M. J. Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size. Mol. Cell Biol. 2005, 25(5), 1869-1878.
64. Chan, T. O.; Rittenhouse, S. E.; Tsichlis, P. N. AKT/PKB and other D3 phosphoinositide-regulated kinases: Kinase activation by phosphoinositide- dependent phosphorylation. Ann. Rev. Biochem. 1999, 68, 965-1014.
65. Masure, S.; Haefner, B.; Wesselink, J. J.; Hoefnagel, E.; Mortier, E.; Verhasselt, P.; Tuytelaars, A.; Gordon, R.; Richardson, A. Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. Euro. J. Biochem. 1999, 265, 353-360.
66. Milburn, C. C.; Deak, M.; Kelly, S. M.; Price, N. C.; Alessi, D. R.; VanAalten, D. M. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem. J. 2003, 375, 531-538.
67. Thomas, C. C.; Deak, M.; Alessi, D. R.; van-Aalten, D. M. High resolution structure of the pleckstrin homology domain of protein kinase b/akt bound to phosphatidylinositol (3,4,5)-trisphosphate. Curr. Biol. 2002, 12, 1256-1262.
68. Milburn, C. C.; Deak, M.; Kelly, S. M.; Price, N. C.; Alessi, D. R.; VanAalten, D. M. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem. J. 2003, 375, 531-538.
69. Yang, J.; Cron, P.; Good, V. M.; Thompson, V.; Hemmings, B. A.; Barford, D. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nature Struc. Biol. 2002, 9, 940-944.
70. Yang, J.; Cron, P.; Thompson, V.; Good, V. M.; Hess, D.; Hemmings, B. A.; Barford, D. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 2002, 9, 1227-1240.
71. Garcia Echeverria, C.; Traxler, P.; Evans, D. B. ATP site-directed competitive and irreversible inhibitors of protein kinases. Med. Res. Rev. 2000, 20, 28-57.
72. Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Protein Kinase Inhibitors: Insights into Drug Design from Structure. Science 2004, 303, 1800-1805.
73. Nagar, B.; Bornmann, W. G.; Pellicena, P.; Schindler, T.; Veach, D. R.; Miller, W. T.; Clarkson, B.; Kuriyan, J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002, 62, 4236-4243.
74. Schindler, T.; Bornmann, W.; Pellicena, P.; Miller, W. T.; Clarkson, B.; Kuriyan, J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000, 289, 1938-1942.
75. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nature Struc. Biol. 2002, 9(4), 268-272.
76. Manley, P. W.; Bold, G.; Bruggen, J.; Fendrich, G.; Furet, P.; Mestan, J.; Schnell, C.; Stolz, B.; Meyer, T.; Meyhack, B.; Stark, W.; Strauss, A.; Wood, J. Advances in the structural biology, VEGF-R kinase inhibitors for design and clinical development of the treatment of angiogenesis. Bio. Et Biophys. Acta Prot. Proteom. 2004, 1697(1-2) Special Iss. SI, 17-27.
77. Alessi, D. R.; James, S. R.; Downes, C. P.; Holmes, A. B.; Gaffney, P. R. J.; Reese, C. B.; Cohen, P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha. Curr. Biol. 1997, 7, 261-269.
78. Stokoe, D.; Stephens, L. R.; Copeland, T.; Gaffney, P. R. J.; Reese, C. B.; Painter, G. F.; Holmes, A. B.; McCormick, F.; Hawkins, P. T. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997, 277, 567-570.
79. Yu, D.; Hung, M. C. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000, 19, 6115-6121.
80. Shin, I.; Edl, J.; Biswas, S.; Lin, P. C.; Mernaugh, R.; Arteaga, C. L. Proapoptotic activity of cell-permeable anti-Akt single-chain antibodies. Cancer Res. 2005, 65, 2815-2824.
81. Li, Q.; Zhu, G. D. Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr. Top. Med. Chem. 2002, 2, 939-971.
82. Breitenlechner, C. B.; Wegge, T.; Berillon, L.; Graul, K.; Marzenell, K.; Friebe, W. G.; Thomas, U.; Schumacher, R.; Huber, R.; Engh, R. A.; Masjost, B. Structure-based optimization of novel azepane derivatives as PKB inhibitors. J. Med. Chem. 2004, 47, 1375-1390.
83. Chijiwa, T.; Mishima, A.; Hagiwara, M.; Sano, M.; Hayashi, K.; Inoue, T.; Naito, K.; Toshioka, T.; Hidaka, H. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J. Biol. Chem. 1990, 265, 5267-5272.
84. Reuveni, H.; Livnah, N.; Geiger, T.; Klein, S.; Ohne, O.; Cohen, I.; Benhar, M.; Gellerman, G.; Levitzki, A. Toward a PKB inhibitor: modification of a selective PKA inhibitor by rational design. Biochemistry 2002, 41, 10304-10314.
85. Collins, I.; Caldwell, J.; Fonseca, T.; Donald, A.; Bavetsias, V.; Hunter, L. K.; Garrett, M. D.; Rowlands, M. G.; Aherne, G. W.; Davies, T. G.; Berdini, V.; Woodhead, S. J.; Davis, D.; Seavers, L. C. A.; Wyatt, P. G.; Workman, P.; McDonald, E. Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B. Bioorg. Med. Chem. 2006, 14(4), 1255-1273.
86. Li, Q.; Li, T.; Zhu, G. -D.; Gong, J.; Claibone, A.; Dalton, C.; Luo, Y.; Johnson, E. F.; Shi, Y.; Liu, X.; Klinghofer, V.; Bauch, J. L.; Marsh, K. C.; Bouska, J. J.; Arries, S.; De Jong, R.; Oltersdorf, T.; Stoll, V. S.; Jakob, C. G.; Rosenberg, S. H.; Giranda, V. L. Discovery of trans-3,4′- bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett. 2006, 16, 1679-1685.
87. Li, Q.; Woods, K. W.; Thomas, S.; Zhu, G. -D.; Packard, G.; Fisher, J.; Li, T.; Gong, J.; Dinges, J.; Song, X.; Abrams, J.; Luo, Y.; Johnson, E. F.; Shi, Y.; Liu, X.; Klinghofer, V.; Des Jong, R.; Oltersdorf, T.; Stoll, V. S.; Jakob, C. G.; Rosenberg, S. H.; Giranda, V. L. Synthesis and structure-activity relationship of 3,4′-bispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer. Bioorg. Med. Chem. Lett. 2006, 16, 2000-2007.
88. Zhu, G.-D.; Gong, J.; Claiborne, A.; Woods, K. W.; Gandhi, V. B.; Thomas, S.; Luo, Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone, S. R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.; Shoemaker, A.; Oleksijew, A.; Stoll, V. S.; De Jong, R.; Oltersdorf, T.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity. Bioorg. Med. Chem. Lett. 2006, 16, 3150-3155.
89. Thomas, S. A.; Li, T.; Woods, K. W.; Song, X.; Packard, G.; Fischer, J. P.; Diebold, R. B.; Liu, X.; Shi, Y.; Klinghofer, V.; Johnson, E. F.; Bouska, J. J.; Olson, A.; Guan, R.; Magnone, S. R.; Marsh, K.; Luo, Y.; Rosenberg, S. H.; Giranda, V. L.; Li, Q. Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase. Bioorg. Med. Chem. Lett. 2006, 16, 3740-3744.
90. Zhu, G. -D.; Gandhi, V. B.; Gong, J.; Luo, Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone, S. R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.; Shoemaker, A.; Oleksijew, A.; Jarvis, K.; Park, C.; Jong, R. D.; Oltersdorf, T.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers. Bioorg. Med. Chem. Lett. 2006, 16, 3424-3429.
91. Woods, K. W.; Fischer, J. P.; Claiborne, A.; Li, T.; Thomas, S. A.; Zhu, G.-D.; Diebold, R. B.; Liu, X.; Shi, Y.; Klinghofer, V.; Han, E. K.; Guan, R.; Magnone, S. R.; Johnson, E. F.; Bouska, J. J.; Olson, A. M.; Jong, R. d.; Oltersdorf, T.; Luo, Y.; Rosenberg, S. H.; Giranda, V. L.; Li, Q. Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors. Bioorg. Med. Chem. Lett. 2006, 14, 6832-6846.
92. 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.; Oleksijew, A.; Mitten, M. J.; Shi, Y.; Guan, R.; McGonigal, T. P.; Klinghofer, V.; Johnson, E. F.; Leverson, J. D.; Bouska, J. J.; Mamo, M.; Smith, R. A.; Gramling-Evans, E. E.; Zinker, B. A.; Mika, A. K.; Nguyen, P. T.; Oltersdorf, T.; Rosenberg, S. H.; Li, Q.; Giranda, V. L. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol. Cancer Ther. 2005, 4, 977-986.
93. Shi, Y.; Liu, X.; Han, E. K.; Guan, R.; Shoemaker, A. R.; Oleksijew, A.; Woods, K. W.; Fisher, J. P.; Klinghofer, V.; Lasko, L.; McGonigal, T.; Li, Q.; Rosenberg, S. H.; Giranda, V. L.; Luo, Y. Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of Akt in vitro and in vivo. Neoplasia (United States) 2005, 7, 992-1000.
94. Lin, X.; Murray, J. M.; Rico, A. C.; Wang, M. X.; Chu, D. T.; Zhou, Y.; Del Rosario, M.; Kaufman, S.; Ma, S.; Fang, E.; Crawford, K.; Jefferson, A. B. Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies. Bioorg. Med. Chem. Lett. 2006, 16, 4163-4168.
95. Ko, J. H.; Yeon, S. W.; Ryu, J. S.; Kim, T. -K.; Song, E. -H.; You, H. -J.; Park, R. -A.; Ryu, C. -K. Synthesis and biological evaluation of 5-arylamino-6-chloro-1H-indazole-4,7-diones as inhibitors of protein kinase B/Akt. Bioorg. Med. Chem. Lett. 2006, 16, 6001-6005.
96. Gills, J. J.; Dennis, P. A. The development of phosphatidylinositol ether lipid analogues as inhibitors of the serine/threonine kinase, Akt. Expert Opin. Invest. Drugs 2004, 13, 787-797.
97. Powis, G.; Aksoy, I. A.; Melder, D. C.; Aksoy, S.; Eichinger, H.; Fauq, A. H.; Kozikowski, A. P. D-3-deoxy-3-substituted myo-inositol analogues as inhibitors of cell growth. Cancer Chemother. Pharmacol. 1991, 29, 95-104.
98. Kozikowski, A. P.; Kiddle, J. J.; Frew, T.; Berggren, M.; Powis, G. Synthesis and biology of 1D-3-deoxyphosphatidylinositol: a putative antimetabolite of phosphatidylinositol-3-phosphate and an inhibitor of cancer cell colony formation. J. Med. Chem. 1995, 38, 1053-1056.
99. Qiao, L.; Nan, F.; Kunkel, M.; Gallegos, A.; Powis, G.; Kozikowski, A. P. 3-Deoxy-D-myo-inositol 1-phosphate, 1-phosphonate, and ether lipid analogues as inhibitors of phosphatidylinositol-3-kinase signaling and cancer cell growth. J. Med. Chem. 1998, 41, 3303-3306.
100. Castillo, S. S.; Brognard, J.; Petukhov, P. A.; Zhang, C. Y.; Tsurutani, J.; Granville, C. A.; Li, M.; Jung, M.; West, K. A.; Gills, J. G.; Kozikowski, A. P.; Dennis, P. A. Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues. Cancer Res. 2004, 64, 2782-2792.
101. Alfaro-Lopez, J.; Yuan, W.; Phan, B. C.; Kamath, J.; Lou, Q.; Lam, K. S.; Hruby, V. J. Discovery of a novel series of potent and selective substrate-based inhibitors of p60c-src protein tyrosine kinase: conformational and topographical constraints in peptide design. J. Med. Chem. 1998, 41, 2252-2260.
102. Harris, T. E.; Persaud, S. J.; Saermark, T.; Jones, P. M. Effects of myristoylated pseudosubstrate protein kinase C peptide inhibitors on insulin secretion. Biochem. Soc. Trans. 1995, 23, 187S
103. Luo, Y.; Smith, R. A.; Guan, R.; Liu, X. S.; Klinghofer, V.; Shen, J. W.; Hutchins, C.; Richardson, P.; Holzman, T.; Rosenberg, S. H.; Giranda, V. L. Pseudosubstrate peptides inhibit Akt and induce cell growth inhibition. Biochemistry 2004, 43, 1254-1263.
104. Livnah, N. L.; Yechezkel, T.; Salitra, Y.; Perlmutter, B.; Ohne, O.; Cohen, I.; Litman, P.; Senderowitz, H. WO2003/010281.
105. Yang, L.; Dan, H. C.; Sun, M.; Liu, Q. Y.; Sun, X. M.; Feldman, R. I.; Hamilton, A. D.; Polokoff, M.; Nicosia, S. V.; Herlyn, M.; Sebti, S. M.; Cheng, J. Q.; Castillo, S. S.; Brognard, J.; Petukhov, P. A.; Zhang, C.; Tsurutani, J.; Granville, C. A.; Li, M.; Jung, M.; West, K. A.; Gills, J. G.; Kozikowski, A. P.; Dennis, P. A. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 2004, 64, 4394-4399.
106. Feun, L. G.; Blessing, J. A.; Barrett, R. J.; Hanjani, P. A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study. Am. J. Clin. Oncol. 1993, 16, 506-508.
107. Feun, L. G.; Savaraj, N.; Bodey, G. P.; Lu, K.; Yap, B. S.; Ajani, J. A.; Burgess, M. A.; Benjamin, R. S.; McKelvey, E.; Krakoff, I. Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule. Cancer Res. 1984, 44, 3608-3612.
108. Jong, L.; Chao, W. R.; Amin, K.; Laderoute, K.; Orduna, J.; Rice, G. SR13668: A novel natural indole derivative potently suppresses tumor growth and inhibits phospho-Akt both in vitro and in vivo Clinical Cancer Res. 2003, 9 ,16.
109. Zinda, M. J.; Johnson, M. A.; Paul, J. D.; Horn, C.; Konicek, B. W.; Lu, Z. H.; Sandusky, G.; Thomas, J. E.; Neubauer, B. L.; Lai, M. T.; Graff, J. R. AKT-1,-2, and-3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin. Cancer Res. 2001, 7(8), 2475-2479.
110. Hsu, J. H.; Shi, Y.; Hu, L.; Fisher, M.; Franke, T. F.; Lichtenstein, A. Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses. Oncogene 2002, 21, 1391-1400.
111. Brognard, J.; Clark, A. S.; Ni, Y.; Dennis, P. A. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 2001, 61, 3986-3997.
112. Kozikowski, A. P.; Sun, H.; Brognard, J.; Dennis, P. A. Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. J. Am. Chem. Soc. 2003, 125, 1144-1145.
113. Graff, J. R. Emerging targets in the AKT pathway for treatment of androgenin-dependent prostatic adenocarcinoma. Expert Opin. Ther. Targets 2002, 6, 103-113.
114. Yang, Z. Z.; Tschopp, O.; Baudry, A.; Dummler, B.; Hynx, D.; Hemmings, B. A. Physiological functions of protein kinase B/Akt. Biochem. Soc. Trans. 2004, 32, 350-354.
115. Barnett, S. F.; Bilodeau, M. T.; Lindsley, C. W. The Akt/PKB family of protein kinases: A review of small molecule inhibitors and progress towards target validation. Curr. Topics Med. Chem. 2005, 5(2), 109-125.
116. Defeo-Jones, D.; Barnett, S. F.; Fu, S.; Hancock, P. J.; Haskell, K. M.; Leander, K. R.; McAvoy, E.; Robinson, R. G.; Duggan, M. E.; Lindsley, C. W.; Zhao, Z.; Huber, H. E.; Jones, R. E. Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members. Mol. Cancer Ther. 2005, 4(2), 271-279.
117. Zhao, Z.; Duggan, M. E.; Barnett, S. F.; Defeo-Jones, D.; Huber, H. E.; Huff, J. R.; Hartman, G. D.; Leister, W.; Kral, A.; Fu, S.; Hancock, P. J.; Haskell, K. A.; Jones, R. E.; Robinson, R.; Lindsley, C. W. Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors. Bioorg. Med. Chem.Lett., 2005 15, 905-909.
118. Lindsley, C. W.; Bogusky, M. J.; Leister, W. H.; McClain, R. T.; Robinson, R.; Barnett, S. F.; Defeo-Jones, D.; III Ross, C. W.; Hartman, G. D. 'Synthesis and biological evaluation of unnatural canthine alkaloids'. Tetrahedron Lett. 2005, 46, 2779-2782.
119. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nature Structural Biology 2002, 9(4), 268-272.
120. Davidson, W.; Frego, L.; Peet, G. W.; Kroe, R. R.; Labadia, M. E.; Lukas, S. M.; Snow, R. J.; Jakes, S.; Grygon, C. A.; Pargellis, C.; Werneburg, B. G. Discovery and characterization of a substrate selective p38alpha inhibitor. Biochemistry 2004, 43, 11658-11671.
121. Alessi, D. R.; Cuenda, A.; Cohen, P.; Dudley, D. T.; Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 1995, 270(46), 27489-27494.
122. Dudley, D. T.; Pang, L.; Decker, S. J.; Bridges, A. J.; Saltiel, A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA 1995, 92, 7686-7689.
123. Favata, M. F.; Horiuchi, K. Y.; Manos, E. J.; Daulerio, A. J.; Stradley, D. A.; Feeser, W. S.; VanDyk, D. E.; Pitts, W. J.; Earl, R. A.; Hobbs, F.; Copeland, R. A.; Magolda, R. L.; Scherle, P. A.; Trzaskos, J. M. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 1998, 273(29), 18623-18632.
124. Nesterov, A.; Lu, X.; Johnson, M.; Miller, G. J.; Ivashchenko, Y.; Kraft, A. S. Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. J. Biol. Chem. 2001, 276, 10767-10774.
125. Rokhlin, O. W.; Guseva, N. V.; Tagiyev, A. F.; Glover, R. A.; Cohen, M. B. Caspase-8 activation is necessary but not sufficient for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in the prostatic carcinoma cell line LNCaP. Prostate 2002, 52(1), 1-11.
126. Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. A Specific Inhibitor of Phosphatidylnositol 3-Kinase, 2-(4-Morpholinyl)-8-Phenyl-4h-1- Benzopyran-4-One (Ly294002). J. Biol. Chem. 1994, 269, 5241-5248.
127. Kim, D.; Cheng, G. Z.; Lindsley, C. W.; Yang, H.; Cheng, J. Q. 'Targeting phosphatidylinositol-3 kinase/Akt pathway for cancer therapy'. Curr. Opin. Invest. Drugs 2005, 6, 1250-1258.
128. Stahl, J. M.; Sharma, A.; Cheung, M.; Zimmerman, M.; Cheng, J. Q.; Bosenberg, M. W.; Kester, M.; Sandirasegarane, L.; Robertson, G. P. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004, 64, 7002-7010.