Developments in selective small molecule ATP-competitive inhibitors targeting the serine/threonine kinase Akt/PKB

Mini-Reviews in Medicinal Chemistry

Volumn 11, Issue 13, 2011, Pages 1093-1107

  Wang, P ^a,b   Zhang, L ^b   Hao, Q ^a   Zhao, G ^a  

^a SHANDONG UNIVERSITY   (China)

^b SHANDONG UNIVERSITY   (China)

Author keywords

Akt; ATP competitive inhibitors; PI3K Akt signaling pathway; Selective

Indexed keywords

4 [2 (4 AMINO 1,2,5 OXADIAZOL 3 YL) 1 ETHYL 7 (3 PIPERIDINYLMETHOXY) 1H IMIDAZO[4,5 C]PYRIDIN 4 YL] 2 METHYL 3 BUTYN 2 OL; A 443654; A 674563; ADENOSINE TRIPHOSPHATE; CCT 128930; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE B BETA; PROTEIN KINASE B INHIBITOR; RAPAMYCIN; UNCLASSIFIED DRUG;

CLINICAL TRIAL (TOPIC); COMPETITIVE INHIBITION; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG SELECTIVITY; HEMATOLOGIC MALIGNANCY; HUMAN; HYPERGLYCEMIA; IC 50; NONHUMAN; PROSTATE CARCINOMA; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SINGLE DRUG DOSE; SOLID TUMOR; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DISCOVERY; HUMANS; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; SMALL MOLECULE LIBRARIES;

EID: 80054079305     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/138955711797655380     Document Type: Review

References (93)

1. Wendel, H.G.; de Stanchina, E.; Fridman, J.S.; Malina, A.; Ray, S.; Kogan, S.; Cordon-Cardo, C.; Pelletier, J.; Lowe, S.W. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature, 2004, 428, 332-7.
2. Omar, B.; Zmuda-Trzebiatowska, E.; Manganiello, V.; Goransson, O.; Degerman, E. Regulation of AMP-activated protein kinase by cAMP in adipocytes: Roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis. Cell Signal., 2009, 21, 760-6.
3. Lawlor, M.A.; Alessi, D.R. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell. Sci., 2001, 114, 2903-10.
4. Tang, J.M.; He, Q.Y.; Guo, R.X.; Chang, X.J. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer, 2006, 51, 181-91.
5. Al-Bazz, Y.O.; Underwood, J.C.; Brown, B.L.; Dobson, P.R. Prognostic significance of Akt, phospho-Akt and BAD expression in primary breast cancer. Eur. J. Cancer, 2009, 45, 694-704.
6. Zhang, M.; Fang, X.; Liu, H.; Guo, R.; Wu, X.; Li, B.; Zhu, F.; Ling, Y.; Griffith, B.N.; Wang, S.; Yang, D. Bioinformatics-based discovery and characterization of an AKT-selective inhibitor 9- chloro-2-methylellipticinium acetate (CMEP) in breast cancer cells. Cancer Lett., 2007, 252, 244-58.
7. Zhang, M.; Fang, X.; Liu, H.; Wang, S.; Yang, D. Blockade of AKT activation in prostate cancer cells with a small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP). Biochem. Pharmacol., 2007, 73, 15-24.
8. Shtilbans, V.; Wu, M.; Burstein, D.E. Current overview of the role of Akt in cancer studies via applied immunohistochemistry. Ann. Diagn. Pathol., 2008, 12, 153-60.
9. Pal, S.K.; Reckamp, K.; Yu, H.; Figlin, R.A. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin. Investig. Drugs, 2010, 19, 1355-66.
10. Clinicaltrials.gov. Search for clinical trials. Use Perifosine as search term. Available from: http://clinicaltrials.gov/ct2/results?term=Perifosine (Accessed September 29, 2010).
11. Clinicaltrials.gov. Search for clinical trials. Use MK-2206 as search item. Available from: http://clinicaltrials.gov/ct2/results?term=MK-2206 (Accessed September 29, 2010).
12. Clinicaltrials.gov. Search for clinical trials. Use RX-0201 as search item. Available from: http://clinicaltrials.gov/ct2/results?term=RX-0201 (Accessed September 29, 2010).
13. Clinicaltrials.gov. Search for clinical trials. Use GSK690693 as search item. Available from: http://clinicaltrials.gov/ct2/results?term=GSK690693 (Accessed September 29, 2010).
14. Crouthamel, M.C.; Kahana, J.A.; Korenchuk, S.; Zhang, S.Y.; Sundaresan, G.; Eberwein, D.J.; Brown, K.K.; Kumar, R. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin. Cancer Res., 2009, 15, 217-25.
15. Clinicaltrials.gov. Search for clinical trials. Use GSK2141795 as search item. Available from: http://clinicaltrials.gov/ct2/results?term=GSK2141795 (Accessed September 29, 2010).
16. Clinicaltrials.gov. Search for clinical trials. Use XL-418 as search item. Available from: http://clinicaltrials.gov/ct2/results?term=XL-418 (Accessed September 29, 2010).
17. Davies, T.G.; Verdonk, M.L.; Graham, B.; Saalau-Bethell, S.; Hamlett, C.C.F.; McHardy, T.; Collins, I.; Garrett, M.D.; Workman, P.; Woodhead, S.J.; Jhoti, H.; Barford, D. A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J. Mo. Biol., 2007, 367, 882-94.
18. Pearce, L.R.; Komander, D.; Alessi, D.R. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol., 2010, 11, 9-22.
19. Reuveni, H.; Livnah, N.; Geiger, T.; Kleid, 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, 10304-14.
20. Collins, I.; Caldwell, J.; Fonseca, T.; Donald, A.; Bavetsias, V.; Hunter, L.J.; Garrett, M.D.; Rowlands, M.G.; Aherne, G.W.; Davies, T.G.; Berdini, V.; Woodhead, S.J.; Davis, D.; Seavers, L.C.; Wyatt, P.G.; Workman, P.; McDonald, E. Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B. Bioorg. Med. Chem., 2006, 14, 1255-73.
21. Saxty, G.; Woodhead, S.J.; Berdini, V.; Davies, T.G.; Verdonk, M.L.; Wyatt, P.G.; Boyle, R.G.; Barford, D.; Downham, R.; Garrett, M.D.; Carr, R.A. Identification of inhibitors of protein kinase B using fragment-based lead discovery. J. Med. Chem., 2007, 50, 2293-6.
22. 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. Nat. Struct. Biol., 2002, 9, 940-4.
23. 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, 575-89.
24. 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. Top. Med. Chem., 2005, 5, 109-25.
25. Hanada, M.; Feng, J.; Hemmings, B.A. Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim. Biophys. Acta, 2004, 1697, 3-16.
26. Liao, J.J. Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem., 2007, 50, 409-24.
27. Donald, A.; McHardy, T.; Rowlands, M.G.; Hunter, L.J.; Davies, T.G.; Berdini, V.; Boyle, R.G.; Aherne, G.W.; Garrett, M.D.; Collins, I. Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design. J. Med. Chem., 2007, 50, 2289-92.
28. Lindsley, C.W.; Barnett, S.F.; Yaroschak, M.; Bilodeau, M.T.; Layton, M.E. Recent progress in the development of ATPcompetitive and allosteric Akt kinase inhibitors. Curr. Top. Med. Chem., 2007, 7, 1349-63.
29. Lindsley, C.W.; Barnett, S.F.; Layton, M.E.; Bilodeau, M.T. The PI3K/Akt pathway: recent progress in the development of ATPcompetitive and allosteric Akt kinase inhibitors. Curr. Cancer Drug Targets, 2008, 8, 7-18.
30. Cheng, G.Z.; Park, S.; Shu, S.; He, L.; Kong, W.; Zhang, W.; Yuan, Z.; Wang, L.H.; Cheng, J.Q. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr. Cancer Drug Targets, 2008, 8, 2-6.
31. Lindsley, C.W. The Akt/PKB Family of Protein Kinases: A Review of Small Molecule Inhibitors and Progress Towards Target Validation: A 2009 Update. Curr. Top. Med. Chem., 2010, 10, 458-77.
32. Kawauchi, K.; Ogasawara, T.; Yasuyama, M.; Otsuka, K.; Yamada, O. The PI3K/Akt Pathway as a Target in the Treatment of Hematologic Malignancies. Anti-Cancer Agents Med. Chem., 2009, 9, 550-9.
33. Martelli, A.M.; Tabellini, G.; Bortul, R.; Nyakern, M.; Tazzari, P.L.; Evangelisti, C.; Cocco, L. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway as a therapeutic target for the treatment of human acute myeloid leukemia (AML). Curr. Signal Transduct. Ther., 2007, 2, 246-56.
34. Dos Santos, C.; Recher, C.; Demur, C.; Payrastre, B. The PI3K/Akt/mTOR pathway: a new therapeutic target in the treatment of acute myeloid leukemia. Bull. Cancer, 2006, 93, 445-7.
35. West, K.A.; Castillo, S.S.; Dennis, P.A. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist. Updat, 2002, 5, 234-48.
36. Rong, S.B.; Hu, Y.; Enyedy, I.; Powis, G.; Meuillet, E.J.; Wu, X.; Wang, R.; Wang, S.; Kozikowski, A.P. Molecular modeling studies of the Akt PH domain and its interaction with phosphoinositides. J. Med. Chem., 2001, 44, 898-908.
37. Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 2005, 307, 1098-101.
38. Bayascas, J.R.; Alessi, D.R. Regulation of Akt/PKB Ser473 phosphorylation. Mol. Cell, 2005, 18, 143-5.
39. Okuzumi, T.; Fiedler, D.; Zhang, C.; Gray, D.C.; Aizenstein, B.; Hoffman, R.; Shokat, K.M. Inhibitor hijacking of Akt activation. Nat. Chem. Biol., 2009, 5, 484-93.
40. Wang, R.W.; Brattain, M.G. AKT can be activated in the nucleus. Cell. Signal., 2006, 18, 1722-31.
41. Huang, H.J.; Tindall, D.J. Dynamic FoxO transcription factors. J. Cell Sci., 2007, 120, 2479-87.
42. Cully, M.; You, H.; Levine, A.J.; Mak, T.W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer, 2006, 6, 184-92.
43. Datta, S.R.; Dudek, H.; Tao, X.; Masters, S.; Fu, H.; Gotoh, Y.; Greenberg, M.E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 1997, 91, 231-41.
44. Ichijo, H.; Nishida, E.; Irie, K.; ten Dijke, P.; Saitoh, M.; Moriguchi, T.; Takagi, M.; Matsumoto, K.; Miyazono, K.; Gotoh, Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science, 1997, 275, 90-4.
45. Pan, J.J.; Chang, Q.S.; Wang, X.; Son, Y.; Zhang, Z.; Chen, G.; Luo, J.; Bi, Y.Y.; Chen, F.; Shi, X.L. Reactive Oxygen Species-Activated Akt/ASK1/p38 Signaling Pathway in Nickel Compound-Induced Apoptosis in BEAS 2B Cells. Chem. Res. Toxicol., 2010, 23, 568-77.
46. Li, J.; Yuan, J. Caspases in apoptosis and beyond. Oncogene, 2008, 27, 6194-206.
47. Cardone, M.H.; Roy, N.; Stennicke, H.R.; Salvesen, G.S.; Franke, T.F.; Stanbridge, E.; Frisch, S.; Reed, J.C. Regulation of cell death protease caspase-9 by phosphorylation. Science, 1998, 282, 1318-21.
48. Cantarelli, B.; Duca, L.; Blanchevoye, C.; Poitevin, S.; Martiny, L.; Debelle, L. Elastin peptides antagonize ceramide-induced apoptosis. FEBS Lett., 2009, 583, 2385-91.
49. Zheng, T.S.; Meng, X.Z.; Wang, J.B.; Chen, X.; Yin, D.L.; Liang, Y.J.; Song, X.A.; Pan, S.H.; Jiang, H.C.; Liu, L.X. PTEN- and p53-Mediated Apoptosis and Cell Cycle Arrest by FTY720 in Gastric Cancer Cells and Nude Mice. J. Cell. Biochem., 2010, 111, 218-28.
50. Qu, Y.; Wang, J.H.; Sim, M.S.; Liu, B.Y.; Giuliano, A.; Barsoum, J.; Cui, X.J. Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells. Breast Cancer Res. Treat., 2010, 121, 311-21.
51. Doble, B.W.; Woodgett, J.R. GSK-3: tricks of the trade for a multitasking kinase. J. Cell Sci., 2003, 116, 1175-86.
52. Frame, S.; Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochemical Journal, 2001, 359, 1-16.
53. Grimes, C.A.; Jope, R.S. The multifaceted roles of glycogen synthase kinase 3 beta in cellular signaling. Prog. Neurobiol., 2001, 65, 391-426.
54. Li, Y.-C.; Gao, W.-J. GSK-3' activity and hyperdopaminedependent behaviors. Neurosci. Biobehav. Rev., 2010, 35, 645-54.
55. Martelli, A.M.; Evangelisti, C.; Chiarini, F.; Grimaldi, C.; Cappellini, A.; Ognibene, A.; McCubrey, J.A. The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogenesis. Biochim Biophys Acta, 2010, 1803, 991-1002.
56. Tamburini, J.; Green, A.S.; Chapuis, N.; Bardet, V.; Lacombe, C.; Mayeux, P.; Bouscary, D. Targeting translation in acute myeloid leukemia A new paradigm for therapy? Cell Cycle, 2009, 8, 3893-9.
57. Bai, X.C.; Jiang, Y. Key factors in mTOR regulation. Cell. Mol. Life Sci., 2010, 67, 239-53.
58. Salmena, L.; Carracedo, A.; Pandolfi, P.P. Tenets of PTEN tumor suppression. Cell, 2008, 133, 403-14.
59. Stocker, H.; Andjelkovic, M.; Oldham, S.; Laffargue, M.; Wymann, M.P.; Hemmings, B.A.; Hafen, E. Living with lethal PIP3 levels: Viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science, 2002, 295, 2088-91.
60. Stambolic, V.; Suzuki, A.; de la Pompa, J.L.; Brothers, G.M.; Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J.M.; Siderovski, D.P.; Mak, T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998, 95, 29-39.
61. Hou, P.; Ji, M.J.; Xing, M.Z. Association of PTEN Gene Methylation With Genetic Alterations in the Phosphatidylinositol 3-Kinase/AKT Signaling Pathway in Thyroid Tumors. Cancer, 2008, 113, 2440-7.
62. Fine, B.; Hodakoski, C.; Koujak, S.; Su, T.; Saal, L.H.; Maurer, M.; Hopkins, B.; Keniry, M.; Sulis, M.L.; Mense, S.; Hibshoosh, H.; Parsons, R. Activation of the PI3K Pathway in Cancer Through Inhibition of PTEN by Exchange Factor P-REX2a. Science, 2009, 325, 1261-5.
63. Suwa, A.; Kurama, T.; Shimokawa, T. SHIP2 and its involvement in various diseases. Expert Opin. Ther. Targets, 2010, 14, 727-37.
64. Kalesnikoff, J.; Sly, L.M.; Hughes, M.R.; Büchse, T.; Rauh, M.J.; Cao, L.P.; Lam, V.; Mui, A.; Huber, M.; Krystal, G. The role of SHIP in cytokine-induced signaling. Rev. Physiol., Biochem. Pharmacol., 2003, 149, 87-103.
65. Mistafa, O.; Ghalali, A.; Kadekar, S.; Hogberg, J.; Stenius, U. Purinergic Receptor-mediated Rapid Depletion of Nuclear Phosphorylated Akt Depends on Pleckstrin Homology Domain Leucine-rich Repeat Phosphatase, Calcineurin, Protein Phosphatase 2A, and PTEN Phosphatases. J. Biol. Chem., 2010, 285, 27900-10.
66. Brognard, J.; Newton, A.C. PHUPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol. Metab., 2008, 19, 223-30.
67. Heerding, D.A.; Rhodes, N.; Leber, J.D.; Clark, T.J.; Keenan, R.M.; Lafrance, L.V.; Li, M.; Safonov, I.G.; Takata, D.T.; Venslavsky, J.W.; Yamashita, D.S.; Choudhry, A.E.; Copeland, R.A.; Lai, Z.; Schaber, M.D.; Tummino, P.J.; Strum, S.L.; Wood, E.R.; Duckett, D.R.; Eberwein, D.; Knick, V.B.; Lansing, T.J.; McConnell, R.T.; Zhang, S.; Minthorn, E.A.; Concha, N.O.; Warren, G.L.; Kumar, R. Identification of 4-(2-(4-amino-1,2,5- oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]o xy}-1Himidazo[ 4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J. Med. Chem., 2008, 51, 5663-79.
68. 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.; Kahana, J.A.; Geske, R.S.; Kleymenova, E.V.; Choudhry, A.E.; Lai, Z.; Leber, J.D.; Minthorn, E.A.; Strum, S.L.; Wood, E.R.; Huang, P.S.; Copeland, R.A.; Kumar, R. Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity. Cancer Res., 2008, 68, 2366-74.
69. Levy, D.S.; Kahana, J.A.; Kumar, R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood, 2009, 113, 1723-9.
70. Rouse, M. Aminofurazans as potent inhibitors of AKT kinase. Bioorg. Med. Chem. Lett., 2009, 19, 1508-11.
71. Zhu, G.D.; Gandhi, V.B.; Gong, J.; Thomas, S.; Woods, K.W.; Song, X.; Li, T.; Diebold, R.B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E.F.; Bouska, J.; Olson, A.; Marsh, K.C.; Stoll, V.S.; Mamo, M.; Polakowski, J.; Campbell, T.J.; Martin, R.L.; Gintant, G.A.; Penning, T.D.; Li, Q.; Rosenberg, S.H.; Giranda, V.L. Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. J. Med. Chem., 2007, 50, 2990-3003.
72. 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, 977-86.
73. Li, Q.; Li, T.; Zhu, G.-D.; Gong, J.; Claibone, A.; Dalton, C.; Luo, Y.; Johnson, E.F.; Shi, Y.; Liu, X. 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, 1679-85.
74. Li, Q.; Woods, K.W.; Thomas, S.; Zhu, G.-D.; Packard, G.; Fisher, J.; Li, T.; Gong, J.; Dinges, J.; Song, X. Synthesis and structure activity relationship of 3,4'- ispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer. Bioorg. Med. Chem. Lett., 2006, 16, 2000-7.
75. Zhu, G.-D.; Gong, J.; Claiborne, A.; Woods, K.W.; Gandhi, V.B.; Thomas, S.; Luo, Y.; Liu, X.; Shi, Y.; Guan, R. Isoquinoline pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity. Bioorg. Med. Chem. Lett., 2006, 16, 3150-5.
76. 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. Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors. Bioorg. Med. Chem., 2006, 14, 6832-46.
77. Zhu, G.-D.; Gandhi, V.B.; Gong, J.; Luo, Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone, S.R.; Klinghofer, V.; Johnson, E.F. Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers. Bioorg. Med. Chem. Lett., 2006, 16, 3424-9.
78. Zhu, G.-D.; Gong, J.; Gandhi, V.B.; Woods, K.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E.F.; Stoll, V.S. Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt. Bioorg. Med. Chem., 2007, 15, 2441-52.
79. Thomas, S.A.; Li, T.; Woods, K.W.; Song, X.; Packard, G.; Fischer, J.P.; Diebold, R.B.; Liu, X.; Shi, Y.; Klinghofer, V. 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, 3740-4.
80. Lin, H.; Yamashita, D.S.; Zeng, J.; Xie, R.; Wang, W.; Nidarmarthy, S.; Luengo, J.I.; Rhodes, N.; Knick, V.B.; Choudhry, A.E. 2,3,5-Trisubstituted pyridines as selective AKT inhibitors Part I: Substitution at 2-position of the core pyridine for ROCK1 selectivity. Bioorg. Med. Chem. Lett., 2010, 20, 673-8.
81. Lin, H.; Yamashita, D.S.; Xie, R.; Zeng, J.; Wang, W.; Leber, J.; Safonov, I.G.; Verma, S.; Li, M.; LaFrance, L. Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines. Bioorg. Med. Chem. Lett., 2010, 20, 684-8.
82. Lin, H.; Yamashita, D.S.; Zeng, J.; Xie, R.; Verma, S.; Luengo, J.I.; Rhodes, N.; Zhang, S.; Robell, K.A.; Choudhry, A.E. 2,3,5- Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg. Med. Chem. Lett., 2010, 20, 679-83.
83. Lin, X.; Murray, J.M.; Rico, A.C.; Wang, M.X.; Chu, D.T.; Zhou, Y.; Rosario, M.D.; Kaufman, S.; Ma, S.; Fang, E. Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies. Bioorg. Med. Chem. Lett., 2006, 16, 4163-8.
84. Seefeld, M.A.; Rouse, M.B.; McNulty, K.C.; Sun, L.; Wang, J.; Yamashita, D.S.; Luengo, J.I.; Zhang, S.; Minthorn, E.A.; Concha, N.O. Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 2244-8.
85. Zeng, Q.; Bourbeau, M.P.; Wohlhieter, G.E.; Yao, G.; Monenschein, H.; Rider, J.T.; Lee, M.R.; Zhang, S.; Lofgren, J.; Freeman, D.; Li, C.; Tominey, E.; Huang, X.; Hoffman, D.; Yamane, H.; Tasker, A.S.; Dominguez, C.; Viswanadhan, V.N.; Hungate, R.; Zhang, X. 2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics. Bioorg. Med. Chem. Lett., 2010, 20, 1652-6.
86. Zeng, Q.; Allen, J.G.; Bourbeau, M.P.; Wang, X.; Yao, G.; Tadesse, S.; Rider, J.T.; Yuan, C.C.; Hong, F.T.; Lee, M.R.; Zhang, S.; Lofgren, J.A.; Freeman, D.J.; Yang, S.; Li, C.; Tominey, E.; Huang, X.; Hoffman, D.; Yamane, H.K.; Fotsch, C.; Dominguez, C.; Hungate, R.; Zhang, X. Azole-based inhibitors of AKT/PKB for the treatment of cancer. Bioorg. Med. Chem. Lett., 2010, 20, 1559-64.
87. Subramanian, R.; Lee, M.R.; Allen, J.G.; Bourbeau, M.P.; Fotsch, C.; Hong, F.T.; Tadesse, S.; Yao, G.M.; Yuan, C.C.; Surapaneni, S.; Skiles, G.L.; Wang, X.H.; Wohlhieter, G.E.; Zeng, Q.P.; Zhou, Y.H.; Zhu, X.C.; Li, C. Cytochrome P450-Mediated Epoxidation of 2-Aminothiazole-Based AKT Inhibitors: Identification of Novel GSH Adducts and Reduction of Metabolic Activation through Structural Changes Guided by in Silico and in vitro Screening. Chem. Res. Toxicol., 2010, 23, 653-63.
88. Caldwell, J.J.; Davies, T.G.; Doiiald, A.R.R.; McHardy, T.; Rowlands, M.G.; Aherne, G.W.; HLinter, L.K.; Taylor, K.; Ruddle, R.; Raynaud, F.I.; Verdonk, M.; Workman, P.; Garrett, M.D.; Collins, I. Identification of 4-(4-aminopiperidin-1-yl)-7Hpyrrolo[ 2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J. Med. Chem., 2008, 51, 2147-57.
89. Donald, A.; McHardy, T.; Rowlands, M.G.; Hunter, L.J.K.; Davies, T.G.; Berdini, V.; Boyle, R.G.; Aherne, G.W.; Garrett, M.D.; Collins, I. Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design. J. Med. Chem., 2007, 50, 2289-92.
90. McHardy, T.; Caldwell, J.J.; Cheung, K.M.; Hunter, L.J.; Taylor, K.; Rowlands, M.; Ruddle, R.; Henley, A.; de Haven Brandon, A.; Valenti, M.; Davies, T.G.; Fazal, L.; Seavers, L.; Raynaud, F.I.; Eccles, S.A.; Aherne, G.W.; Garrett, M.D.; Collins, I. Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J. Med. Chem., 2010, 53, 2239-49.
91. Lippa, B.; Pan, G.; Corbett, M.; Li, C.; Kauffman, G.S.; Pandit, J.; Robinson, S.; Wei, L.; Kozina, E.; Marr, E.S. Synthesis and structure based optimization of novel Akt inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 3359-63.
92. Freeman-Cook, K.D.; Autry, C.; Borzillo, G.; Gordon, D.; Barbacci-Tobin, E.; Bernardo, V.; Briere, D.; Clark, T.; Corbett, M.; Jakubczak, J.; Kakar, S.; Knauth, E.; Lippa, B.; Luzzio, M.J.; Mansour, M.; Martinelli, G.; Marx, M.; Nelson, K.; Pandit, J.; Rajamohan, F.; Robinson, S.; Subramanyam, C.; Wei, L.; Wythes, M.; Morris, J. Design of Selective, ATP-Competitive Inhibitors of Akt. J. Med. Chem., 2010, 53, 4615-22.
93. Breitenlechner, C.B.; Friebe, W.G.; Brunet, E.; Werner, G.; Graul, K.; Thomas, U.; Kunkele, K.P.; Schafer, W.; Gassel, M.; Bossemeyer, D.; Huber, R.; Engh, R.A.; Masjost, B. Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants. J. Med. Chem., 2005, 48, 163-70.