Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

Proceedings of the National Academy of Sciences of the United States of America

Volumn 113, Issue 13, 2016, Pages E1796-E1805

  Harriman, Geraldine ^a   Greenwood, Jeremy ^b   Bhat, Sathesh ^b   Huang, Xinyi ^c   Wang, Ruiying ^d   Paul, Debamita ^d   Tong, Liang ^d   Saha, Asish K ^e   Westlin, William F ^a   Kapeller, Rosana ^a   Harwood, H James ^a  

^a Nimbus Therapeutics   (United States)

^b SCHRÖDINGER INC   (United States)

^c Pharmaron Beijing Co Ltd   (China)

^d Och Spine at New York Presbyterian Hospitals   (United States)

^e BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Acetyl CoA carboxylase; Enzyme inhibition; Fatty liver disease

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; GLUCOSE; HEMOGLOBIN A1C; INSULIN; LIGASE INHIBITOR; MALONYL COENZYME A; ND 630; PHOSPHOPEPTIDE; UNCLASSIFIED DRUG; ACACA PROTEIN, HUMAN; ACACB PROTEIN, HUMAN; ENZYME INHIBITOR; ND-630; PYRIMIDINONE DERIVATIVE; THIOPHENE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANINE MODEL; CARBOHYDRATE DIET; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIET INDUCED OBESITY; DIMERIZATION; DOSE RESPONSE; DRUG BINDING SITE; DRUG DOSE; DRUG EFFICACY; DRUG SAFETY; DYSLIPIDEMIA; ENZYME ACTIVITY; ENZYME INHIBITION; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; FATTY LIVER; FEMALE; FOOD INTAKE; GLUCOSE BLOOD LEVEL; HEPG2 CELL LINE; HUMAN; HUMAN CELL; HYPERINSULINEMIA; HYPERLEPTINEMIA; IC50; IMPAIRED GLUCOSE TOLERANCE; IN VIVO STUDY; INSULIN RELEASE; INSULIN RESISTANCE; INSULIN SENSITIVITY; MALE; MAXIMUM TOLERATED DOSE; MOLECULAR MODEL; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; PR INTERVAL; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; QRS INTERVAL; RAT; RR INTERVAL; SINUS RHYTHM; SKELETAL MUSCLE; THERMOSTABILITY; WEIGHT GAIN; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; DYSLIPIDEMIAS; HEP-G2 CELL LINE; METABOLISM; MOLECULAR DOCKING; OBESITY; PROTEIN MULTIMERIZATION; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION; ZUCKER RAT;

ACETYL-COA CARBOXYLASE; ANIMALS; DYSLIPIDEMIAS; ENZYME INHIBITORS; FATTY LIVER; FEMALE; HEP G2 CELLS; HUMANS; INSULIN RESISTANCE; MALE; MOLECULAR DOCKING SIMULATION; OBESITY; PROTEIN MULTIMERIZATION; PYRIMIDINONES; RATS, SPRAGUE-DAWLEY; RATS, ZUCKER; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 84962190509     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1520686113     Document Type: Article

References (56)

1. Harwood HJ, Jr (2005) Treating the metabolic syndrome: Acetyl-CoA carboxylase inhibition. Expert Opin Ther Targets 9(2): 267-281.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285(19): 2486-2497.
3. Neuschwander-Tetri BA (2010) Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites. Hepatology 52(2): 774-788.
4. Miller M, et al.; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease (2011) Triglycerides and cardiovascular disease: A scientific statement from the American Heart Association. Circulation 123(20): 2292-2333.
5. Harwood HJ, Jr (2012) The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology 63(1): 57-75.
6. American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Suppl 1): S81-S90.
7. Baenke F, Peck B, Miess H, Schulze A (2013) Hooked on fat: The role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech 6(6): 1353-1363.
8. Mounier C, Bouraoui L, Rassart E (2014) Lipogenesis in cancer progression (review). Int J Oncol 45(2): 485-492.
9. Tong L, Harwood HJ, Jr (2006) Acetyl-coenzyme A carboxylases: Versatile targets for drug discovery. J Cell Biochem 99(6): 1476-1488.
10. Kim KH (1997) Regulation of mammalian acetyl-coenzyme A carboxylase. Annu Rev Nutr 17: 77-99.
11. Tong L (2005) Acetyl-coenzyme A carboxylase: Crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci 62(16): 1784-1803.
12. Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (2006) Regulation of acetyl-CoA carboxylase. Biochem Soc Trans 34(Pt 2): 223-227.
13. Abu-Elheiga L, et al. (2000) The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci USA 97(4): 1444-1449.
14. Widmer J, et al. (1996) Identification of a second human acetyl-CoA carboxylase gene. Biochem J 316(Pt 3): 915-922.
15. Bianchi A, et al. (1990) Identification of an isozymic form of acetyl-CoA carboxylase. J Biol Chem 265(3): 1502-1509.
16. McGarry JD, Brown NF (1997) The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem 244(1): 1-14.
17. McCune SA, Harris RA (1979) Mechanism responsible for 5-(tetradecyloxy)-2-furoic acid inhibition of hepatic lipogenesis. J Biol Chem 254(20): 10095-10101.
18. Fukuda N, Ontko JA (1984) Interactions between fatty acid synthesis, oxidation, and esterification in the production of triglyceride-rich lipoproteins by the liver. J Lipid Res 25(8): 831-842.
19. Harwood HJ, Jr, et al. (2003) Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem 278(39): 37099-37111.
20. Abu-Elheiga L, Matzuk MM, Abo-Hashema KAH, Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291(5513): 2613-2616.
21. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ (2003) Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci USA 100(18): 10207-10212.
22. Savage DB, et al. (2006) Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest 116(3): 817-824.
23. Qi L, et al. (2006) TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312(5781): 1763-1766.
24. Fullerton MD, et al. (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 19(12): 1649-1654.
25. Hoehn KL, et al. (2010) Acute or chronic upregulation ofmitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab 11(1): 70-76.
26. Olson DP, Pulinilkunnil T, Cline GW, Shulman GI, Lowell BB (2010) Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake. Proc Natl Acad Sci USA 107(16): 7598-7603.
27. Corbett JW, et al. (2010) Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg Med Chem Lett 20(7): 2383-2388.
28. Bourbeau MP, Bartberger MD (2015) Recent advances in the development of acetyl-CoA carboxylase (ACC) inhibitors for the treatment of metabolic disease. J Med Chem 58(2): 525-536.
29. Griffith DA, et al. (2014) Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes. J Med Chem 57(24): 10512-10526.
30. Glund S, et al. (2012) Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice. Diabetologia 55(7): 2044-2053.
31. Zhang H, Tweel B, Li J, Tong L (2004) Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure 12(9): 1683-1691.
32. Zhang H, Tweel B, Tong L (2004) Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop. Proc Natl Acad Sci USA 101(16): 5910-5915.
33. Zhang H, Yang Z, Shen Y, Tong L (2003) Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science 299(5615): 2064-2067.
34. Shen Y, Volrath SL, Weatherly SC, Elich TD, Tong L (2004) A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product. Mol Cell 16(6): 881-891.
35. Cho YS, et al. (2010) Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. Biochem Biophys Res Commun 391(1): 187-192.
36. Wei J, Tong L (2015) Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. Nature 526(7575): 723-727.
37. Tong L (2013) Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 70(5): 863-891.
38. Cornachione AS, Benedini-Elias PC, Polizello JC, Carvalho LC, Mattiello-Sverzut AC (2011) Characterization of fiber types in different muscles of the hindlimb in female weanling and adult Wistar rats. Acta Histochem Cytochem 44(2): 43-50.
39. Etgen GJ, Oldham BA (2000) Profiling of Zucker diabetic fatty rats in their progression to the overt diabetic state. Metabolism 49(5): 684-688.
40. Harada N, et al. (2007) Hepatic de novo lipogenesis is present in liver-specific ACC1-deficient mice. Mol Cell Biol 27(5): 1881-1888.
41. Harmancey R, Vasquez HG, Guthrie PH, Taegtmeyer H (2013) Decreased long-chain fatty acid oxidation impairs postischemic recovery of the insulin-resistant rat heart. FASEB J 27(10): 3966-3978.
42. Kolwicz SC, Jr, et al. (2012) Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res 111(6): 728-738.
43. Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49(2): 377-389.
44. Abel R, Young T, Farid R, Berne BJ, Friesner RA (2008) Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J Am Chem Soc 130(9): 2817-2831.
45. Shelley JC, et al. (2007) Epik: A software program for pK(a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 21(12): 681-691.
46. Friesner RA, et al. (2006) Extra Precision Glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49(21): 6177-6196.
47. Raymer B, et al. (2009) Synthesis and characterization of a BODIPY-labeled derivative of Soraphen A that binds to acetyl-CoA carboxylase. Bioorg Med Chem Lett 19(10): 2804-2807.
48. Vedadi M, et al. (2006) Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination. Proc Natl Acad Sci USA 103(43): 15835-15840.
49. Harriman GC, Masse CE, Harwood HJ, Jr, Baht S, Greenwood JR (2013) Acetyl-CoA carboxylase inhibitors and uses thereof. US patent publication US 2013/0123231.
50. Jump DB, Torres-Gonzalez M, Olson LK (2011) Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation. Biochem Pharmacol 81(5): 649-660.
51. Saha AK, Kurowski TG, Colca JR, Ruderman NB (1994) Lipid abnormalities in tissues of the KKAy mouse: Effects of pioglitazone on malonyl-CoA and diacylglycerol. Am J Physiol 267(1 Pt 1): E95-E101.
52. Chandler CE, et al. (2003) CP-346086: An MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. J Lipid Res 44(10): 1887-1901.
53. Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol 276: 307-326.
54. Brünger AT, et al. (1998) Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54(Pt 5): 905-921.
55. Adams PD, et al. (2002) PHENIX: Building new software for automated crystallographic structure determination. Acta Crystallogr D Biol Crystallogr 58(Pt 11): 1948-1954.
56. Emsley P, Cowtan K (2004) Coot: Model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60(Pt 12 Pt 1): 2126-2132.