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A-769662

Description of A-769662: A-769662 is a potent, reversible AMP-activated protein kinase (AMPK) activator with an EC50 of 0.8 μM.A-769662 displays selectivity towards β1 subunit-containing heterotrimers.

A-769662 is a new activator of AMP-activated protein kinase (AMPK). Unlike other pharmacological activators, it directly activates native rat AMPK by mimicking both effects of AMP, i.e. allosteric activation and inhibition of dephosphorylation. It was found that it has no effect on the isolated alpha subunit kinase domain, with or without the associated autoinhibitory domain, or on interaction of glycogen with the beta subunit glycogen-binding domain. Although it mimics actions of AMP, it has no effect on binding of AMP to the isolated Bateman domains of the gamma subunit. The addition of A-769662 to mouse embryonic fibroblasts or primary mouse hepatocytes stimulates phosphorylation of acetyl-CoA carboxylase (ACC), effects that are completely abolished in AMPK-alpha1(-/-)alpha2(-/-) cells but not in TAK1(-/-) mouse embryonic fibroblasts. Phosphorylation of AMPK and ACC in response to A-769662 is also abolished in isolated mouse skeletal muscle lacking LKB1, a major upstream kinase for AMPK in this tissue. However, in HeLa cells, which lack LKB1 but express the alternate upstream kinase calmodulin-dependent protein kinase kinase-beta, phosphorylation of AMPK and ACC in response to A-769662 still occurs. These results show that in intact cells, the effects of A-769662 are independent of the upstream kinase utilized.  (see: Göransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem. 2007 Nov 9;282(45):32549-60. http://www.ncbi.nlm.nih.gov/pubmed/17855357)

Current developer:   

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2: Leclerc I, Sun G, Morris C, Fernandez-Millan E, Nyirenda M, Rutter GA. AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells. Diabetologia. 2011 Jan;54(1):125-34. Epub 2010 Oct 13. PubMed PMID: 20938634.

3: Santidrián AF, González-Gironès DM, Iglesias-Serret D, Coll-Mulet L, Cosialls AM, de Frias M, Campàs C, González-Barca E, Alonso E, Labi V, Viollet B, Benito A, Pons G, Villunger A, Gil J. AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. Blood. 2010 Oct 21;116(16):3023-32. Epub 2010 Jul 27. PubMed PMID: 20664053.

4: Rajamohan F, Harris MS, Frisbie RK, Hoth LR, Geoghegan KF, Valentine JJ, Reyes AR, Landro JA, Qiu X, Kurumbail RG. Escherichia coli expression, purification and characterization of functional full-length recombinant alpha2beta2gamma3 heterotrimeric complex of human AMP-activated protein kinase. Protein Expr Purif. 2010 Oct;73(2):189-97. Epub 2010 May 6. PubMed PMID: 20451617.

5: Sid B, Miranda L, Vertommen D, Viollet B, Rider MH. Stimulation of human and mouse erythrocyte Na(+)-K(+)-2Cl(-) cotransport by osmotic shrinkage does not involve AMP-activated protein kinase, but is associated with STE20/SPS1-related proline/alanine-rich kinase activation. J Physiol. 2010 Jul 1;588(Pt 13):2315-28. Epub 2010 May 4. PubMed PMID: 20442269; PubMed Central PMCID: PMC2915509.

6: Miranda L, Carpentier S, Platek A, Hussain N, Gueuning MA, Vertommen D, Ozkan Y, Sid B, Hue L, Courtoy PJ, Rider MH, Horman S. AMP-activated protein kinase induces actin cytoskeleton reorganization in epithelial cells. Biochem Biophys Res Commun. 2010 Jun 4;396(3):656-61. Epub 2010 May 8. PubMed PMID: 20438708.

7: Sopjani M, Bhavsar SK, Fraser S, Kemp BE, Föller M, Lang F. Regulation of Na+-coupled glucose carrier SGLT1 by AMP-activated protein kinase. Mol Membr Biol. 2010 Apr;27(2-3):137-44. PubMed PMID: 20334581.

8: Fazakerley DJ, Holman GD, Marley A, James DE, Stöckli J, Coster AC. Kinetic evidence for unique regulation of GLUT4 trafficking by insulin and AMP-activated protein kinase activators in L6 myotubes. J Biol Chem. 2010 Jan 15;285(3):1653-60. Epub 2009 Nov 13. PubMed PMID: 19915010; PubMed Central PMCID: PMC2804323.

9: García-García C, Fumarola C, Navaratnam N, Carling D, López-Rivas A. AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators. Biochem Pharmacol. 2010 Mar 15;79(6):853-63. Epub 2009 Nov 5. PubMed PMID: 19896469.

10: Fujimoto A, Akifusa S, Kamio N, Hirofuji T, Nonaka K, Yamashita Y. Involvement of mTOR in globular adiponectin-induced generation of reactive oxygen species. Free Radic Res. 2010 Feb;44(2):128-34. PubMed PMID: 19886750.

11: Benziane B, Björnholm M, Lantier L, Viollet B, Zierath JR, Chibalin AV. AMP-activated protein kinase activator A-769662 is an inhibitor of the Na(+)-K(+)-ATPase. Am J Physiol Cell Physiol. 2009 Dec;297(6):C1554-66. Epub 2009 Oct 14. PubMed PMID: 19828836.

12: Treebak JT, Birk JB, Hansen BF, Olsen GS, Wojtaszewski JF. A-769662 activates AMPK beta1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle. Am J Physiol Cell Physiol. 2009 Oct;297(4):C1041-52. Epub 2009 Aug 5. PubMed PMID: 19657063.

13: Dallas ML, Scragg JL, Wyatt CN, Ross F, Hardie DG, Evans AM, Peers C. Modulation of O(2) sensitive K (+) channels by AMP-activated protein kinase. Adv Exp Med Biol. 2009;648:57-63. PubMed PMID: 19536465.

14: Zhou Y, Wang D, Zhu Q, Gao X, Yang S, Xu A, Wu D. Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3-L1 adipogenesis. Biol Pharm Bull. 2009 Jun;32(6):993-8. PubMed PMID: 19483304.

15: Hallows KR, Alzamora R, Li H, Gong F, Smolak C, Neumann D, Pastor-Soler NM. AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells. Am J Physiol Cell Physiol. 2009 Apr;296(4):C672-81. Epub 2009 Feb 11. PubMed PMID: 19211918; PubMed Central PMCID: PMC2670645.

16: Scott JW, van Denderen BJ, Jorgensen SB, Honeyman JE, Steinberg GR, Oakhill JS, Iseli TJ, Koay A, Gooley PR, Stapleton D, Kemp BE. Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes. Chem Biol. 2008 Nov 24;15(11):1220-30. PubMed PMID: 19022182.

17: Glund S, Treebak JT, Long YC, Barres R, Viollet B, Wojtaszewski JF, Zierath JR. Role of adenosine 5'-monophosphate-activated protein kinase in interleukin-6 release from isolated mouse skeletal muscle. Endocrinology. 2009 Feb;150(2):600-6. Epub 2008 Sep 25. PubMed PMID: 18818284.

18: Guigas B, Sakamoto K, Taleux N, Reyna SM, Musi N, Viollet B, Hue L. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life. 2009 Jan;61(1):18-26. Review. PubMed PMID: 18798311; PubMed Central PMCID: PMC2845387.

19: Moreno D, Knecht E, Viollet B, Sanz P. A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism. FEBS Lett. 2008 Jul 23;582(17):2650-4. Epub 2008 Jun 30. PubMed PMID: 18593584.

20: Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008 Jun 1;412(2):211-21. PubMed PMID: 18387000.

21: Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J. 2008 Jan 15;409(2):449-59. PubMed PMID: 17995453.

22: Göransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem. 2007 Nov 9;282(45):32549-60. Epub 2007 Sep 12. PubMed PMID: 17855357; PubMed Central PMCID: PMC2156105.

23: Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D. 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 Nov 9;282(45):32539-48. Epub 2007 Aug 29. PubMed PMID: 17728241.

24: Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 2006 Jun;3(6):403-16. PubMed PMID: 16753576.