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Research Articles

In search of AKT kinase inhibitors as anticancer agents: structure-based design, docking, and molecular dynamics studies of 2,4,6-trisubstituted pyridines

, , ORCID Icon, &
Pages 423-442 | Received 23 Nov 2016, Accepted 11 Jan 2017, Published online: 10 Feb 2017

References

  • Addie, M. , Ballard, P. , Buttar, D. , Crafter, C. , Currie, G. , Davies, B. R. , … Ruston, L. (2013). Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. Journal of Medicinal Chemistry , 56 , 2059–2073.10.1021/jm301762v
  • Altomare, D. A. , & Testa, J. R. (2005). Perturbations of the AKT signaling pathway in human cancer. Oncogene , 24 , 7455–7464.10.1038/sj.onc.1209085
  • Arnold, K. , Bordoli, L. , Kopp, J. , & Schwede, T. (2006). The SWISS-MODEL workspace: A web-based environment for protein structure homology modelling. Bioinformatics , 22 , 195–201.10.1093/bioinformatics/bti770
  • Berendsen, H. J. C. , Postma, J. P. M. , van Gunsteren, W. F. , DiNola, A. , & Haak, J. R. (1984). Molecular dynamics with coupling to an external bath. The Journal of Chemical Physics , 81 , 3684–3690.10.1063/1.448118
  • Berman, H. M. , Westbrook, J. , Feng, Z. , Gilliland, G. , Bhat, T. N. , Weissig, H. , … Bourne, P. E. (2000). The protein data bank. Nucleic Acids Research , 28 , 235–242.10.1093/nar/28.1.235
  • Bianco, R. , Melisi, D. , Ciardiello, F. , & Tortora, G. (2006). Key cancer cell signal transduction pathways as therapeutic targets. European Journal of Cancer , 42 , 290–294.
  • Brodbeck, D. , Cron, P. , & Hemmings, B. A. (1999). A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. Journal of Biological Chemistry , 274 , 9133–9136.10.1074/jbc.274.14.9133
  • Burris, H. A. (2013). Overcoming acquired resistance to anticancer therapy: Focus on the PI3K/AKT/mTOR pathway. Cancer Chemotherapy and Pharmacology , 71 , 829–842.10.1007/s00280-012-2043-3
  • Charifson, P. S. , Corkery, J. J. , Murcko, M. A. , & Walters, W. P. (1999). Consensus scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. Journal of Medicinal Chemistry , 42 , 5100–5109.10.1021/jm990352k
  • Chen, V. B. , Arendall, W. B. , Headd, J. J. , Keedy, D. A. , Immormino, R. M. , Kapral, G. J. , … Richardson, D. C. (2010). MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallographica Section D: Biological Crystallography , 66 , 12–21.10.1107/S0907444909042073
  • Cheng, J. Q. , Lindsley, C. W. , Cheng, G. Z. , Yang, H. , & Nicosia, S. V. (2005). The Akt/PKB pathway: Molecular target for cancer drug discovery. Oncogene , 24 , 7482–7492.10.1038/sj.onc.1209088
  • Chin, Y. R. , Yoshida, T. , Marusyk, A. , Beck, A. H. , Polyak, K. , & Toker, A. (2014). Targeting Akt3 signaling in triple-negative breast cancer. Cancer Research , 74 , 964–973.10.1158/0008-5472.CAN-13-2175
  • Cho, J. H. , Robinson, J. P. , Arave, R. A. , Burnett, W. J. , Kircher, D. A. , Chen, G. , … Holmen, S. L. (2015). AKT1 activation promotes development of melanoma metastases. Cell Reports , 13 , 898–905.
  • Darden, T. , York, D. , & Pedersen, L. (1993). Particle mesh Ewald: An Nlog(N) method for Ewald sums in large systems. The Journal of Chemical Physics , 98 , 10089–10092.10.1063/1.464397
  • Davies, T. G. , Verdonk, M. L. , Graham, B. , Saalau-Bethell, S. , Hamlett, C. C. F. , McHardy, T. , … Barford, D. (2007). A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. Journal of Molecular Biology , 367 , 882–894.10.1016/j.jmb.2007.01.004
  • DeLano, W. L. (2007). The PyMOL molecular graphics system, delano scientific . Palo Alto, CA: LLC.
  • Dummler, B. , & Hemmings, B. A. (2007). Physiological roles of PKB/Akt isoforms in development and disease. Biochemical Society Transactions , 35 , 231–235.10.1042/BST0350231
  • Fife, C. M. , McCarroll, J. A. , & Kavallaris, M. (2014). Movers and shakers: Cell cytoskeleton in cancer metastasis. British Journal of Pharmacology , 171 , 5507–5523.10.1111/bph.2014.171.issue-24
  • Fresno Vara, J. A. , Casado, E. , de Castro, J. , Cejas, P. , Belda-Iniesta, C. , & González-Barón, M. (2004). PI3K/Akt signalling pathway and cancer. Cancer Treatment Reviews , 30 , 193–204.10.1016/j.ctrv.2003.07.007
  • Friesner, R. A. , Banks, J. L. , Murphy, R. B. , Halgren T. A. , Klicic, J. J. , Mainz, D. T. , … Shenkin, P. S. (2004). Glide- a new approach for rapid, accurate docking and scoring. Journal of Medicinal Chemistry, 47, 1739–1749.
  • Gasteiger, J. , & Marsili, M. (1978). A new model for calculating atomic charges in molecules. Tetrahedron Letters , 19 , 3181–3184.10.1016/S0040-4039(01)94977-9
  • Grabinski, N. , Bartkowiak, K. , Grupp, K. , Brandt, B. , Pantel, K. , & Jücker, M. (2011). Distinct functional roles of Akt isoforms for proliferation, survival, migration and EGF-mediated signalling in lung cancer derived disseminated tumor cells. Cellular Signalling , 23 , 1952–1960.
  • Han, Z. , Wu, K. , Shen, H. , Li, C. , Han, S. , Hong, L. , … Fan, D. (2008). Akt1/protein kinase Bα is involved in gastric cancer progression and cell proliferation. Digestive Diseases and Sciences , 53 , 1801–1810.10.1007/s10620-007-9824-2
  • Hernández-Campos, A. , Velázquez-Martínez, I. , Castillo, R. , López-Vallejo, F. , Jia, P. , Yu, Y. , … Medina-Franco, J. L. (2010). Docking of protein kinase B inhibitors: Implications in the structure-based optimization of a novel scaffold. Chemical Biology and Drug Design , 76 , 269–276.
  • Héron-Milhavet, L. , Franckhauser, C. , Rana, V. , Berthenet, C. , Fisher, D. , Hemmings, B. A. , … Lamb, N. J. C. (2006). Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Molecular and Cellular Biology , 26 , 8267–8280.10.1128/MCB.00201-06
  • Homeyer, N. , & Gohlke, H. (2012). Free energy calculations by the molecular mechanics Poisson−Boltzmann surface area method. Molecular Informatics , 31 , 114–122.10.1002/minf.v31.2
  • Hou, T. , Wang, J. , Li, Y. , & Wang, W. (2010). Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. Journal of Chemical Information and Modeling , 51 , 69–82.
  • Hutchinson, J. N. , Jin, J. , Cardiff, R. D. , Woodgett, J. R. , & Muller, W. J. (2004). Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Research , 1 , 3171–3178.10.1158/0008-5472.CAN-03-3465
  • Jordan, M. A. , & Wilson, L. (2004). Microtubules as a target for anticancer drugs. Nature Reviews. Cancer , 4 , 253–265.10.1038/nrc1317
  • Kopp, J. , & Schwede, T. (2006). The SWISS-MODEL repository: New features and functionalities. Nucleic Acids Research , 34 , D315–D318.10.1093/nar/gkj056
  • Kroemer, R. T. (2007). Structure-based drug design: Docking and scoring. Current Protein and Peptide Science , 8 , 312–328.10.2174/138920307781369382
  • Kumar, C. C. , & Madison, V. (2005). AKT crystal structure and AKT-specific inhibitors. Oncogene , 24 , 7493–7501.10.1038/sj.onc.1209087
  • Kumari, R. , Kumar, R. , & Lynn, A. (2014). g-mmpbsa -A GROMACS tool for high-throughput MM-PBSA calculations. Journal of Chemical Information and Modeling , 54 , 1951–1962.10.1021/ci500020m
  • Levitzki, A. , & Klein, S. (2010). Signal transduction therapy of cancer. Molecular Aspects of Medicine , 31 , 287–329.10.1016/j.mam.2010.04.001
  • Liby, T. A. , Spyropoulos, P. , Buff Lindner, H. , Eldridge, J. , Beeson, C. , Hsu, T. , & Muise-Helmericks, R. C. (2012). Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells. International Journal of Cancer , 130 , 532–543.10.1002/ijc.v130.3
  • Lindorff-Larsen, K. , Piana, S. , Palmo, K. , Maragakis, P. , Klepeis, J. L. , Dror, R. O. , & Shaw, D. E. (2010). Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins , 78 , 1950–1958.
  • Lindsley, C. W. , Barnett, S. F. , Yaroschak, M. , Bilodeau, M. T. , & Layton, M. E. (2007). Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Current Topics in Medicinal Chemistry , 7 , 1349–1363.
  • Luo, J. , Manning, B. D. , & Cantley, L. C. (2003). Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell , 4 , 257–262.10.1016/S1535-6108(03)00248-4
  • Manning, B. D. , & Cantley, L. C. (2007). AKT/PKB signaling: Navigating downstream. Cell , 129 , 1261–1274.10.1016/j.cell.2007.06.009
  • Manning, G. , Whyte, D. B. , Martinez, R. , Hunter, T. , & Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science , 298 , 1912–1934.10.1126/science.1075762
  • Mattmann, M. E. , Stoops, S. L. , & Lindsley, C. W. (2011). Inhibition of Akt with small molecules and biologics: Historical perspective and current status of the patent landscape. Expert Opinion on Therapeutic Patents , 21 , 1309–1338.10.1517/13543776.2011.587959
  • Medina-Franco, J. L. , Giulianotti, M. A. , Yu, Y. , Shen, L. , Yao, L. , & Singh, N. (2009). Discovery of a novel protein kinase B inhibitor by structure-based virtual screening. Bioorganic & Medicinal Chemistry Letters , 19 , 4634–4638.10.1016/j.bmcl.2009.06.078
  • Meuillet, E. J. (2011). Novel inhibitors of AKT: Assessment of a different approach targeting the pleckstrin homology domain. Current Medicinal Chemistry , 18 , 2727–2742.10.2174/092986711796011292
  • Morris, G. M. , Huey, R. , Lindstrom, W. , Sanner, M. F. , Belew, R. K. , Goodsell, D. S. , & Olson, A. J. (2009). AutoDock4 and AUTODOCKTOols4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry , 30 , 2785–2791.10.1002/jcc.v30:16
  • Nakatani, K. , Sakaue, H. , Thompson, D. A. , Weigel, R. J. , & Roth, R. A. (1999). Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochemical and Biophysical Research Communications , 257 , 906–910.10.1006/bbrc.1999.0559
  • Parrinello, M. , & Rahman, A. (1980). Crystal structure and pair potentials: A molecular-dynamics study. Physical Review Letters , 45 , 1196–1199.10.1103/PhysRevLett.45.1196
  • Polivka, J. , & Janku, F. (2014). Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacology & Therapeutics , 142 , 164–175.10.1016/j.pharmthera.2013.12.004
  • Porta, C. , Paglino, C. , & Mosca, A. (2014). Targeting PI3K/Akt/mTOR signaling in cancer. Frontiers in Oncology , 4 , 1–11.
  • Rouse, M. B. , Seefeld, M. A. , Leber, J. D. , McNulty, K. C. , Sun, L. , Miller, W. H. , … Heerding, D. A. (2009). Aminofurazans as potent inhibitors of AKT kinase. Bioorganic and Medicinal Chemistry Letters , 19 , 1508–1511.10.1016/j.bmcl.2009.01.002
  • Sale, E. M. , & Sale, G. J. (2008). Protein kinase B: Signalling roles and therapeutic targeting. Cellular and Molecular Life Sciences , 65 , 113–127.10.1007/s00018-007-7274-9
  • Saxty, G. , Woodhead, S. J. , Berdini, V. , Davies, T. G. , Verdonk, M. L. , Wyatt, P. G. , … Carr, R. A. (2007). Identification of inhibitors of protein kinase B using fragment-based lead discovery. Journal of Medicinal Chemistry , 50 , 2293–2296.10.1021/jm070091b
  • Schrödinger Release 2015-4: Glide version 6.9 . (2015). New York, NY: Schrödinger, LLC.
  • Schrödinger Release 2015-4: Maestro version 10.4 . (2015). New York, NY: Schrödinger, LLC.
  • Schrödinger Release 2015-4: Protein Preparation Wizard; Epik version 3.4 . (2015). New York, NY : Schrödinger, LLC.
  • Schröndiger Release 2015-4: Prime version 4.2 . (2015). New York, NY: Schrödinger, LLC.
  • Siegel, R. L. , Miller, K. D. , & Jemal, A. (2016). Cancer statistics. CA Cancer Journal for Clinicians , 66 , 7–30.10.3322/caac.v66.1
  • Song, G. , Ouyang, G. , & Bao, S. (2005). The activation of Akt/PKB signaling pathway and cell survival. Journal of Cellular and Molecular Medicine , 9 , 59–71.10.1111/jcmm.2005.9.issue-1
  • Sousa, A. W. , & Vranken, W. F. (2012). ACPYPE – AnteChamber PYthon parser interface. BMC Research Notes , 5 , 1–8.
  • Trott, O. , & Olson, A. J. (2010). AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry , 31 , 455–461.
  • Van Der Spoel, D. , Lindahl, E. , Hess, B. , Groenhof, G. , Mark, A. E. , & Berendsen, H. J. C. (2005). GROMACS: Fast, flexible, and free. Journal of Computational Chemistry , 26 , 1701–1718.10.1002/(ISSN)1096-987X
  • Wang, C. , Nguyen, P. H. , Pham, K. , Huynh, D. , Le, T.-B. N. , Wang, H. , … Luo, R. (2016). Calculating protein-ligand binding affinities with MMPBSA: Method and error analysis. Journal of Computational Chemistry , 37 , 2436–2446.10.1002/jcc.v37.27
  • Wavefunction Inc . (2010). Spartan version 10. Irvine, CA: Author.
  • Woods, K. W. , Fischer, J. P. , Claiborne, A. , Li, T. , Thomas, S. A. , Zhu, G. D. , … Li, Q. (2006). Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors. Bioorganic and Medicinal Chemistry , 14 , 6832–6846.10.1016/j.bmc.2006.06.047
  • Workman, P. , Al-Lazikani, B. , & Clarke, P. A. (2013). Genome-based cancer therapeutics: Targets, kinase drug resistance and future strategies for precision oncology. Current Opinion in Pharmacology , 13 , 486–496.10.1016/j.coph.2013.06.004
  • Xu, P.-Z. , Chen, M.-L. , Jeon, S.-M. , Peng, X. , & Hay, N. (2012). The effect Akt2 deletion on tumor development in Pten(+/−) mice. Oncogene , 31 , 518–526.10.1038/onc.2011.243
  • WHO – Cancer . (2016). Retrieved November 8, 2016, from http://www.who.int/mediacentre/factsheets/fs297/en/; http://www.who.int/cancer/en/
  • Yang, J. , Cron, P. , Good, V. M. , Thompson, V. , Hemmings, B. A. , & Barford, D. (2002). Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nature Structural Biology , 9 , 940–944.10.1038/nsb870
  • Zhang, J. , Yang, P. L. , & Gray, N. S. (2009). Targeting cancer with small molecule kinase inhibitors. Nature Reviews Cancer , 9 , 28–39.10.1038/nrc2559

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