Screening methods for AMP-activated protein kinase modulators: A patent review

Expert Opinion on Therapeutic Patents

Volumn 25, Issue 3, 2015, Pages 261-277

  Kim, Joungmok ^a   Shin, Joonsoo ^b   Ha, Joohun ^c  

^a Kyung Hee University   (South Korea)

^b ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE   (United States)

^c Kyung Hee University Hospital   (South Korea)

Author keywords

AMP activated protein kinase; AMP activated protein kinase modulators; AMP activated protein kinase structure; Screening methods

Indexed keywords

4 AMINOBUTYRIC ACID B RECEPTOR; 6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; ADENOSINE PHOSPHATE; ADENOSINE TRIPHOSPHATE; ENZYME INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; METFORMIN; PERILIPIN; PHENFORMIN; PHOSPHORIBOSYLAMINOIMIDAZOLECARBOXAMIDE FORMYLTRANSFERASE; PRODRUG; RETINOBLASTOMA PROTEIN; PYRONE DERIVATIVE; THIOPHENE DERIVATIVE;

BINDING SITE; CARBOXY TERMINAL SEQUENCE; CELL DIFFERENTIATION; CELL FUNCTION; CELL PROLIFERATION; CHEMICAL STRUCTURE; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG EFFICACY; DRUG STABILITY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME STRUCTURE; GENE EXPRESSION; HUMAN; MOLECULAR MECHANICS; NONHUMAN; OBESITY; PROTEIN PHOSPHORYLATION; REVIEW; SCREENING; STEM CELL; ANIMAL; DRUG DESIGN; DRUG EFFECTS; ENZYMOLOGY; HOMEOSTASIS; METABOLIC DISEASES; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASMS; PATENT;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; DRUG DESIGN; HOMEOSTASIS; HUMANS; METABOLIC DISEASES; MOLECULAR TARGETED THERAPY; NEOPLASMS; PATENTS AS TOPIC; PYRONES; THIOPHENES;

EID: 84922948457     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2014.995626     Document Type: Review

References (122)

1. Hardie D. AMPK-Sensing energy while talking to other signaling pathways. Cell Metabolism. 2014. Available from: http://dx.doi.org/10.1016/j.cmet.2014.09.013
2. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev 2009;89(3):1025-78
3. Hardie DG. AMP-Activated/ SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007;8(10):774-85
4. Birk JB, Wojtaszewski JF. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle. J Physiol 2006;577(Pt 3):1021-32
5. Salt I, Celler JW, Hawley SA, et al. AMP-Activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J 1998;334(Pt 1):177-87
6. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The active form of the metabolic sensor: AMP-Activated protein kinase (AMPK) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis. Cell Cycle 2009;8(15):2385-98
7. Pinter K, Jefferson A, Czibik G, et al. Subunit composition of AMPK trimers present in the cytokinetic apparatus: implications for drug target identification. Cell Cycle 2012;11(5):917-21
8. Kim M, Shen M, Ngoy S, et al. AMPK isoform expression in the normal and failing hearts. J Mol Cell Cardiol 2012;52(5):1066-73
9. Li C, Liu VW, Chiu PM, et al. Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications. BMC Cancer 2012;12:357
10. Fox MM, Phoenix KN, Kopsiaftis SG, et al. AMP-Activated protein kinase alpha 2 isoform suppression in primary breast cancer alters AMPK growth control and apoptotic signaling. Genes Cancer 2013;4(1-2):3-14
11. Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-Activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 2013;18(4):556-66
12. Hardie DG, Hawley SA, Scott JW. AMP-Activated protein kinasedevelopment of the energy sensor concept. J Physiol 2006;574(Pt 1):7-15
13. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012;13(4):251-62
14. Hardie DG. Sensing of energy and nutrients by AMP-Activated protein kinase. Am J Clin Nutr 2011;93(4):891S-16
15. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011;13(9):1016-23
16. Sriwijitkamol A, Musi N. Advances in the development of AMPK-Activating compounds. Expert Opin Drug Discov 2008;3(10):1167-76
17. Viollet B, Guigas B, Leclerc J, et al. AMP-Activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf) 2009;196(1):81-98
18. Wong AK, Howie J, Petrie JR, Lang CC. AMP-Activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease. Clin Sci (Lond) 2009;116(8):607-20
19. Kumar P, Peers C. AMP-Activated protein kinase: function and dysfunction in health and disease. J Physiol 2006;574(Pt 1):3-6
20. Viollet B, Horman S, Leclerc J, et al. AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol 2010;45(4):276-95
21. Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013;19(12):1649-54
22. Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010;120(7):2355-69
23. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444(7117):337-42
24. Um JH, Park SJ, Kang H, et al. AMP-Activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010;59(3):554-63
25. Turner N, Li JY, Gosby A, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-Activated protein kinase and improve insulin action. Diabetes 2008;57(5):1414-18
26. El-Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000;275(1):223-8
27. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its antidiabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348(Pt3):607-14
28. Zheng J, Ramirez VD. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol 2000;130(5):1115-23
29. Yun H, Ha J. AMP-Activated protein kinase modulators: a patent review (2006-2010). Expert Opin Ther Pat 2011;21(7):983-1005
30. Giordanetto F, Karis D. Direct AMPactivated protein kinase activators: a review of evidence from the patent literature. Expert Opin Ther Pat 2012;22(12):1467-77
31. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115(5):577-90
32. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30(2):214-26
33. Hoppe S, Bierhoff H, Cado I, et al. AMP-Activated protein kinase adapts rRNA synthesis to cellular energy supply. Proc Natl Acad Sci USA 2009;106(42):17781-6
34. Jones RG, Plas DR, Kubek S, et al. AMP-Activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005;18(3):283-93
35. Short JD, Dere R, Houston KD, et al. AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 2010;49(5):429-39
36. Liang J, Shao SH, Xu ZX, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007;9(2):218-24
37. Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem 2006;75:137-63
38. Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330(7503):1304-5
39. Huang X, Wullschleger S, Shpiro N, et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 2008;412(2):211-21
40. Rehman G, Shehzad A, Khan AL, et al. Role of AMP-Activated protein kinase in cancer therapy. Arch Pharm (Weinheim) 2014;347(7):457-68
41. Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 2012;485(7400):661-5
42. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010;22(2):124-31
43. Dunlop EA, Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 2014;36C:121-9
44. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93
45. Feng Y, He D, Yao Z, et al. The machinery of macroautophagy. Cell Res 2014;24(1):24-41
46. Schneider JL, Cuervo AM. Autophagy and human disease: Emerging themes. Curr Opin Genet Dev 2014;26C:16-23
47. Klionsky DJ, Codogno P. The mechanism and physiological function of macroautophagy. J Innate Immun 2013;5(5):427-33
48. Lai K, Killingsworth MC, Lee CS. The significance of autophagy in colorectal cancer pathogenesis and implications for therapy. J Clin Pathol 2014;67(10):854-8
49. Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13(2):132-41
50. Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-Activated protein kinase connects energy sensing to mitophagy. Science 2011;331(6016):456-61
51. Kim J, Kim YC, Fang C, et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 2013;152(1-2):290-303
52. Hawley SA, Davison M, Woods A, et al. Characterization of the AMP-Activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-Activated protein kinase. J Biol Chem 1996;271(44):27879-87
53. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-Activated protein kinase cascade. J Biol 2003;2(4):28
54. Woods A, Dickerson K, Heath R, et al. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-Activated protein kinase in mammalian cells. Cell Metab 2005;2(1):21-33
55. Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-Treated epithelial cells. EMBO J 2009;28(6):677-85
56. Hawley SA, Selbert MA, Goldstein EG, et al. 5-AMP activates the AMPactivated protein kinase cascade, and Ca2 +/calmodulin activates the calmodulindependent protein kinase I cascade, via three independent mechanisms. J Biol Chem 1995;270(45):27186-91
57. Davies SP, Helps NR, Cohen PT, et al. 5-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-Activated protein kinase. studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett 1995;377(3):421-5
58. Oakhill JS, Steel R, Chen ZP, et al. AMPK is a direct adenylate chargeregulated protein kinase. Science 2011;332(6036):1433-5
59. Oakhill JS, Chen ZP, Scott JW, et al. Beta-subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-Activated protein kinase (AMPK). Proc Natl Acad Sci USA 2010;107(45):19237-41
60. Fogarty S, Hawley SA, Green KA, et al. Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem J 2010;426(1):109-18
61. Xiao B, Heath R, Saiu P, et al. Structural basis for AMP binding to mammalian AMP-Activated protein kinase. Nature 2007;449(7161):496-500
62. Xiao B, Sanders MJ, Underwood E, et al. Structure of mammalian AMPK and its regulation by ADP. Nature 2011;472(7342):230-3
63. Xiao B, Sanders MJ, Carmena D, et al. Structural basis of AMPK regulation by small molecule activators. Nat Commun 2013;4:3017 and 991.
64. Chen L, Wang J, Zhang YY, et al. AMP-Activated protein kinase undergoes nucleotide-dependent conformational changes. Nat Struct Mol Biol 2012;19(7):716-18
65. Crute BE, Seefeld K, Gamble J, et al. Functional domains of the alpha1 catalytic subunit of the AMPactivated protein kinase. J Biol Chem 1998;273(52):35347-54
66. Hudson ER, Pan DA, James J, et al. A novel domain in AMP-Activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr Biol 2003;13(10):861-6
67. Xin FJ, Wang J, Zhao RQ, et al. Coordinated regulation of AMPK activity by multiple elements in the alpha-subunit. Cell Res 2013;23(10):1237-40
68. Viana R, Towler MC, Pan DA, et al. A conserved sequence immediately Nterminal to the bateman domains in AMP-Activated protein kinase gamma subunits is required for the interaction with the beta subunits. J Biol Chem 2007;282(22):16117-25
69. Scott JW, Hawley SA, Green KA, et al. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 2004;113(2):274-84
70. Ignoul S, Eggermont J. CBS domains: structure, function, and pathology in human proteins. Am J Physiol Cell Physiol 2005;289(6):C1369-78
71. Oakhill JS, Scott JW, Kemp BE. AMPK functions as an adenylate chargeregulated protein kinase. Trends Endocrinol Metab 2012;23(3):125-32
72. Polekhina G, Gupta A, Michell BJ, et al. AMPK beta subunit targets metabolic stress sensing to glycogen. Curr Biol 2003;13(10):867-71
73. McBride A, Ghilagaber S, Nikolaev A, Hardie DG. The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor. Cell Metab 2009;9(1):23-34
74. University Court of the University Dundee. Hardie G. AMP-Activated protein kinase (AMPK) inhibitor screening assay. WO2004024942; 2004
75. Medical Research Council. Gamblin S, Carling D, et al. Crystal structures of AMPK and uses thereof. WO2009019484; 2009
76. Apfeld J, OConnor G, McDonagh T, et al. The AMP-Activated protein kinase AAK-2 links energy levels and insulinlike signals to lifespan in C. elegans. Genes Dev 2004;18(24):3004-9
77. Elixir Pharmaceuticals, Inc. Apfeld J, OConnor G. AMPK pathway components. WO2004050898; 2004
78. Kuramoto N, Wilkins ME, Fairfax BP, et al. Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase. Neuron 2007;53(2):233-47
79. Lee JH, Koh H, Kim M, et al. Energy-dependent regulation of cell structure by AMP-Activated protein kinase. Nature 2007;447(7147):1017-20
80. Tschape JA, Hammerschmied C, Muhlig-Versen M, et al. The neurodegeneration mutant lochrig interferes with cholesterol homeostasis and appl processing. EMBO J 2002;21(23):6367-76
81. Spasic MR, Callaerts P, Norga KK. Drosophila alicorn is a neuronal maintenance factor protecting against activity-induced retinal degeneration. J Neurosci 2008;28(25):6419-29
82. Yun H, Lee M, Kim SS, et al. Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-Activated protein kinase in DU145 prostate carcinoma. J Biol Chem 2005;280(11):9963-72
83. Kim HS, Hwang JT, Yun H, et al. Inhibition of AMP-Activated protein kinase sensitizes cancer cells to cisplatininduced apoptosis via hyper-induction of p53. J Biol Chem 2008;283(7):3731-42
84. Washington University. Milbrandt J, Dasgupta B. AMPK modulation as a method of regulating stem cell and cancer stem cell proliferation, self-renewal and differentiation. US2010221748; 2010
85. Sztalryd C, Kimmel AR. Perilipins: lipid droplet coat proteins adapted for tissuespecific energy storage and utilization, and lipid cytoprotection. Biochimie 2014;96:96-101
86. Smith CE, Ordovas JM. Update on perilipin polymorphisms and obesity. Nutr Rev 2012;70(10):611-21
87. Dr. Reddys Laboratories LTD. Misra P, Chakrabarti R, et al. Modulation of endogenous AMPK levels for the treatment of obesity. WO2009019600; 2009
88. Panayiotou C, Solaroli N, Karlsson A. The many isoforms of human adenylate kinases. Int J Biochem Cell Biol 2014;49:75-83
89. University of Massachusetts. Corvera S, Wilson-Fritch L. Method of identifying protein kinase modulators and uses thereof. WO2005073400; 2005
90. Genexel-Sein, INC, Korea Advanced Institute of Science and Technology. Chung J. AMPK deficient animals, screening methods, and related therapeutics and diagnostics. WO2009031044; 2009
91. Rigel Pharmaceuticals, Inc. Markovstov V, Hitoshi Y. Whole blood assay for measuring AMPK activation. WO2012094173; 2012
92. Merck Sharp & Dohme Corp., Metabasis Therapeutics, Inc. Novel cyclic benzimidazole derivatives useful antidiabetic agents. WO2010036613; 2010
93. Merck Sharp & Dohme Corp, Metabasis Therapeutics, Inc. Novel cyclic benzimidazole derivatives useful antidiabetic agents. WO2010047982; 2010
94. Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents. WO2014139388; 2014
95. Pfizer, Inc. Indole compounds that activate AMPK. WO2014140704; 2014
96. Debiopharm International SA. Novel AMPK activator. WO2014128549; 2014
97. Sinnett SE, Brenman JE. Past strategies and future directions for identifying AMP-Activated protein kinase (AMPK) modulators. Pharmacol Ther 2014;143(1):111-18
98. Anderson SN, Cool BL, Kifle L, et al. Microarrayed compound screening (microARCS) to identify activators and inhibitors of AMP-Activated protein kinase. J Biomol Screen 2004;9(2):112-21
99. Burns DJ, Kofron JL, Warrior U, et al. Well-less, gel-permeation formats for ultra-HTS. Drug Discov Today 2001;6(Suppl 1(0)):40-7
100. Sabet RS, Marcotte P, Glaser K, et al. Screening for inhibitors of histone deacetylase by incorporating a spraying method to micro-Arrayed compound screening. Comb Chem High Throughput Screen 2004;7(2):93-100
101. Gopalakrishnan SM, Karvinen J, Kofron JL, et al. Application of micro arrayed compound screening (microARCS) to identify inhibitors of caspase-3. J Biomol Screen 2002;7(4):317-23
102. Zhou G, Myers R, Li Y, et al. Role of AMP-Activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108(8):1167-74
103. Machrouhi F, Ouhamou N, Laderoute K, et al. The rational design of a novel potent analogue of the 5-AMP-Activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorg Med Chem Lett 2010;20(22):6394-9
104. Erlanson DA, McDowell RS, OBrien T. Fragment-based drug discovery. J Med Chem 2004;47(14):3463-82
105. Clark M, Meshkat S, Talbot GT, et al. Fragment-based computation of binding free energies by systematic sampling. J Chem Inf Model 2009;49(8):1901-13
106. Clark M, Guarnieri F, Shkurko I, et al. Grand canonical Monte Carlo simulation of ligand-protein binding. J Chem Inf Model 2006;46(1):231-42
107. Sinnett SE, Sexton JZ, Brenman JE. A high throughput assay for discovery of small molecules that bind AMP-Activated protein kinase (AMPK). Curr Chem Genomics Transl Med 2013;7:30-8
108. Cool B, Zinker B, Chiou W, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 2006;3(6):403-16
109. Steinberg GR, ONeill HM, Dzamko NL, et al. Whole body deletion of AMP-Activated protein kinase {beta} 2 reduces muscle AMPK activity and exercise capacity. J Biol Chem 2010;285(48):37198-209
110. Barnes BR, Marklund S, Steiler TL, et al. The 5AMP-Activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. J Biol Chem 2004;279(37):38441-7
111. Burwinkel B, Scott JW, Buhrer C, et al. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-Activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet 2005;76(6):1034-49
112. Li J, Zeng Z, Viollet B, et al. Neuroprotective effects of adenosine monophosphate-Activated protein kinase inhibition and gene deletion in stroke. Stroke 2007;38(11):2992-9
113. Corton JM, Gillespie JG, Hawley SA, et al. 5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-Activated protein kinase in intact cells? Eur J Biochem 1995;229(2):558-65
114. Goransson O, McBride A, Hawley SA, et al. Mechanism of action of A-769662, a valuable tool for activation of AMPactivated protein kinase. J Biol Chem 2007;282(45):32549-60
115. Sanders MJ, Ali ZS, Hegarty BD, et al. Defining the mechanism of activation of AMP-Activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem 2007;282(45):32539-48
116. Scott JW, Ling N, Issa SM, et al. Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chem Biol 2014;21(5):619-27
117. Ducommun S, Ford RJ, Bultot L, et al. Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662. Am J Physiol Endocrinol Metab 2014;306(6):E688-96
118. Timmermans AD, Balteau M, Gelinas R, et al. A-769662 potentiates the effect of other AMP-Activated protein kinase activators on cardiac glucose uptake. Am J Physiol Heart Circ Physiol 2014;306(12):H1619-30
119. Calabrese MF, Rajamohan F, Harris MS, et al. Structural basis for AMPK activation: natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms. Structure 2014;22(8):1161-72
120. Scott JW, van Denderen BJ, Jorgensen SB, et al. Thienopyridone drugs are selective activators of AMPactivated protein kinase beta1-containing complexes. Chem Biol 2008;15(11):1220-30
121. Gomez-Galeno JE, Dang Q, Nguyen TH, et al. A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med Chem Lett 2010;1(9):478-82.
122. Hunter RW, Foretz M, Bultot L, et al. Mechanism of action of compound-13: an alpha1-selective small molecule activator of AMPK. Chem Biol 2014;21(7):866-79