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Akt-Targeted Library

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ChemDiv’s Akt-Targeted Library contains 12,000 compounds.

Akt kinase, which is also known as Protein Kinase B (PKB), is one of the key members of extended serine/threonine protein kinase family. This kinase plays a crucial role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.

Three main Akt isoforms (Akt1, Akt2, and Akt3) have been identified in human cells. The first member is deeply involved in cellular survival pathways by inhibiting apoptotic processes. It is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt1 was originally identified as the oncogene in the transforming retrovirus AKT8. The second isoform, Akt2, is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport. The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. Akt is associated with tumor cell survival, proliferation, and invasiveness. The activation of Akt is also one of the most frequent alterations observed in human cancer and tumor cells. Tumor cells that have constantly active Akt may depend on Akt for survival.
Publications
1 Naihan Xu et al. Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2 J Cell Biol. 2010 August 9; 190(3): 297–305.
2 Enomoto A, Murakami H, Asai N, et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 2005;9(3):389-402; Kim D, Kim S, Koh H, et al. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 2001;15(11):1953-1962; Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR. AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 2001;61(2):589-593.
3 Bos JL. A target for phosphoinositide 3-kinase: Akt/PKB. Trends Biochem Sci. 1995;20:441–442; Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem. 1999;68:965–1014.
4 Murthy S, Tosolini A, Taguchi T, Testa JR. Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization. Cytogenet Cell Genet. 2000;88:38–40.
5 Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT–a major therapeutic target. Biochim Biophys Acta. 2004;1697:3–16.
6 Dummler B, Hemmings BA. Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans. 2007;35:231–235. Yang ZZ, Tschopp O, Baudry A, Dummler B, Hynx D, Hemmings BA. Physiological functions of protein kinase B/Akt. Biochem Soc Trans. 2004;32:350–354.
7 Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24:7455–7464. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86. Testa JR, Tsichlis PN. AKT signaling in normal and malignant cells. Oncogene. 2005;24:7391–7393. Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003;4:257–262. Fresno Vara JA, 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. Vestey SB, Sen C, Calder CJ, Perks CM, Pignatelli M, Winters ZE. Activated Akt expression in breast cancer: correlation with p53, Hdm2 and patient outcome. Eur J Cancer. 2005;41:1017–1025. Dillon RL, White D.E., Muller W.J. The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene. 2007;26:1338–1345. Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008;8:187–198. Tokunaga E, Oki E, Egashira A, Sadanaga N, Morita M, Kakeji Y, Maehara Y. Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets. 2008;8:27–36. Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007;12:104–107. Huang WC, Hung MC. Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009;108:180–194.
8 Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86. Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003;4:257–262. Fresno Vara JA, 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. Bozulic L, Hemmings BA. PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr Opin Cell Biol. 2009. Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6:184–192. Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A. 2005;102:802–807. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005;11:353–361. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004. Vogt PK, Gymnopoulos M, Hart JR. PI 3-kinase and cancer: changing accents. Curr Opin Genet Dev. 2009;19:12–17.
9 Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008;8:187–198. Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007;12:104–107. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5:921–929. Soung YH, Lee JW, Nam SW, Lee JY, Yoo NJ, Lee SH. Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology. 2006;70:285–289. Carpten JD, Faber A.L., Horn C., Donoho G.P., Briggs S.L., Robbins C.M., Hostetter G., Boguslawski S., Moses T.Y., Savage S., Uhlik M., Lin A., Du J., Qian Y.W., Zeckner D.J., Tucker-Kellogg G., Touchman J., Patel K., Mousses S., Bittner M., Schevitz R., Lai M.H., Blanchard K.L., Thomas J.E. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–444.
10 Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005;18:13–24. Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007;25:917–931. Brognard J, Newton AC. PHLPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab. 2008. Brognard J, Niederst M, Reyes G, Warfel N, Newton AC. Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem. 2009;284:15215–15223. Newton AC. Lipid activation of protein kinases. J Lipid Res. 2009;50(Suppl):S266–271.
11 Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007;12:104–107.
12 Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem. 1999;68:965–1014. Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335:1–13. (Pt 1).
Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–365. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211–225.
13 Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335:1–13. (Pt 1). Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem. 1999;68:965–1014.
14 Bellacosa A, Chan T.O., Ahmed N.N., Datta K., Malstrom S., Stokoe D., McCormick F., Feng J., Tsichile P. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene. 1998;17:313–325.
15 Alessi DR, Andjelkovic M., Caudwell B., Cron P., Morrice N., Cohen, P, Hemmings B.A. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15:6541–6551. Chan TO, Tsichlis PN. PDK2: a complex tail in one Akt. Sci STKE. 2001;2001:PE1. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal. 2009;2:pe27.
16 Mora A, Komander D, van Aalten DM, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15:161–170. Bayascas JR. Dissecting the role of the 3- phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle. 2008;7:2978–2982.
17 Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 2003;546:108–112. Chan TO, Tsichlis PN. PDK2: a complex tail in one Akt. Sci STKE. 2001;2001:PE1. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal. 2009;2:pe27. 50. Hresko RC, Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/Protein Kinase B in 3T3- L1 adipocytes. J Biol Chem. 2005;280:40406–40416; Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–1101; Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8:179–183; Yang Q, Inoki K, Ikenoue T, Guan KL. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 2006;20:2820–2832; Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16:1865–1870; Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11:859–871; Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22:159–168; Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006;11:583–589; Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–734; Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, Ibrahim A, Gourlay R, Magnuson MA, Alessi DR. Identification of Protor as a novel Rictor-binding component of mTOR-complex-2. Biochem J. 2007; Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127:125–137; Hietakangas V, Cohen SM. Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth. Genes Dev. 2007;21:632–637; Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007;12:487–502; Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans. 2009;37:217–222.
18 Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–1274.
19 Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–1274.
20 Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA. Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem. 2005;280:1982–1991. Kawase T, Ohki R, Shibata T, Tsutsumi S, Kamimura N, Inazawa J, Ohta T, Ichikawa H, Aburatani H, Tashiro F, Taya Y. PH domainonly protein PHLDA3 is a p53-regulated repressor of Akt. Cell. 2009;136:535–550. Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt. Cell. 2002;111:293–303. Sato S, Fujita N, Tsuruo T. Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci U S A. 2000;97:10832–10837. Du K, Tsichlis PN. Regulation of the Akt kinase by interacting proteins. Oncogene. 2005;24:7401–7409.
21 Altomare, D.A.; Zhang, L.; Deng, J.; Di Cristofano, A.; Klein-Szanto, A.J.; Kumar, R.; Testa, J.R. GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt Clin Cancer Res 2010, 16(2): 486; Carol, H.; Morton, C.L.; Gorlick, R.; et al. Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program Pediatr Blood Cancer 2010, 55(7): 1329; Carol, H.; Lock, R.B.; Houghton, P.J.; Morton, C.L.; Maris, J.M.; Courtright, J.; Kolb, E.A.; Gorlick, R.; Friedman, H.S.; Keir, S.T.; Kang, M.; Reynolds, C.P.; Smith, M.A. Pediatric preclinical testing program (PPTP) evaluation of the Akt inhibitor GSK690693 Proc Am Assoc Cancer Res (AACR) 2009, 50: Abst 3193; 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(1): 217
22 Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC, Chauhan D, Richardson PG, Anderson KC. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006 May 15;107(10):4053-62.
23 Li Z, Tan F, Liewehr DJ, Steinberg SM, Thiele CJ. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst. 2010 Jun 2;102(11):758-70.
24 Li Z, Tan F, Liewehr DJ, Steinberg SM, Thiele CJ. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst. 2010 Jun 2;102(11):758-70.
25 Prous Science, URL: http://www.prous.com.
26 Kohonen, T. (1990) The self-organizing map. Proceedings of the IEEE 78, 1464-80.
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