title: Identification of a novel selective agonist of PPARγ with no promotion of adipogenesis and less inhibition of osteoblastogenesis.
abstract: Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in the regulation of glucose homeostasis and lipid metabolism. However, current PPARγ-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified a small molecular compound, F12016, as a selective PPARγ agonist by virtual screening, which showed moderate PPARγ agonistic activity and binding ability for PPARγ. F12016 did not activate other PPAR subtypes at 30 μM and selectively modulated PPARγ target gene expression. In diabetic KKAy mice, F12016 had insulin-sensitizing and glucose-lowering properties, and suppressed weight gain. In vitro, F12016 effectively increased glucose uptake and blocked cyclin-dependent kinase 5-mediated phosphorylation of PPARγ at Ser273, but slightly triggered adipogenesis and less inhibited osteoblastogenesis than rosiglitazone. Moreover, compared with the full agonist rosiglitazone, F12016 had a distinct group of coregulators and a different predicted binding mode for the PPARγ ligand-binding domain. A site mutation assay confirmed the key epitopes, especially Tyr473 in AF-2. In summary, our study shows that F12016 is a non-TZD, novel selective PPARγ agonist without the classical lipogenic side effects, which may provide a new structural strategy for designing PPARγ ligands with advantages over TZDs.
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Feng
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Ningyu
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Xiaowan
authors.initials: X
authors.lastname: Han
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation; D011485:Protein Binding; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C000606221:2-(2-(1,2-dimethyl-1H-indol-3-yl)-2-oxoacetylamino)benzamide; D001549:Benzamides; D007211:Indoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051360:Cyclin-Dependent Kinase 5
references.citation: J Biol Chem. 2008 Apr 4;283(14):9168-76
references.pmid: 18263587
references.citation: Nat Rev Drug Discov. 2004 Nov;3(11):950-64
references.pmid: 15520817
references.citation: PLoS One. 2012;7(11):e50816
references.pmid: 23226391
references.citation: Structure. 2007 Oct;15(10):1258-71
references.pmid: 17937915
references.citation: Cell Metab. 2005 Jun;1(6):361-70
references.pmid: 16054085
references.citation: Eur J Clin Invest. 2005 Feb;35(2):82-92; discussion 80
references.pmid: 15667578
references.citation: Mol Endocrinol. 2009 Jul;23(7):975-88
references.pmid: 19389808
references.citation: Mol Cell. 2001 Oct;8(4):737-47
references.pmid: 11684010
references.citation: Diabetes. 2008 Sep;57(9):2272-9
references.pmid: 18519799
references.citation: Biochim Biophys Acta. 2007 Aug;1771(8):1094-107
references.pmid: 17459763
references.citation: Biochim Biophys Acta. 2007 Aug;1771(8):926-35
references.pmid: 17433773
references.citation: Mol Cell Biol. 2004 Sep;24(18):8244-54
references.pmid: 15340084
references.citation: Mol Endocrinol. 2003 Apr;17(4):662-76
references.pmid: 12554792
references.citation: Diabetes Obes Metab. 2007 May;9(3):369-78
references.pmid: 17391165
references.citation: Arch Intern Med. 2008 Apr 28;168(8):820-5
references.pmid: 18443256
references.citation: Endocrinology. 2002 Jun;143(6):2376-84
references.pmid: 12021203
references.citation: EMBO Rep. 2004 Feb;5(2):142-7
references.pmid: 14755307
references.citation: PPAR Res. 2007;2007:32696
references.pmid: 17389769
references.citation: Endocr Rev. 2004 Dec;25(6):899-918
references.pmid: 15583022
references.citation: J Clin Endocrinol Metab. 2004 Feb;89(2):463-78
references.pmid: 14764748
references.citation: PLoS One. 2013;8(2):e56451
references.pmid: 23457570
references.citation: Biochim Biophys Acta. 2007 Aug;1771(8):936-51
references.pmid: 17306620
references.citation: Osteoporos Int. 2008 Feb;19(2):129-37
references.pmid: 17901911
references.citation: Nature. 2010 Jul 22;466(7305):451-6
references.pmid: 20651683
references.citation: Nature. 2010 Jul 22;466(7305):443-4
references.pmid: 20651677
references.citation: J Biomol Screen. 2014 Apr;19(4):566-74
references.pmid: 24334278
references.citation: Diabetes Care. 2004 Jan;27(1):256-63
references.pmid: 14693998
references.citation: PPAR Res. 2008;2008:297893
references.pmid: 18795105
references.citation: J Clin Invest. 2006 Mar;116(3):581-9
references.pmid: 16511590
references.citation: Diab Vasc Dis Res. 2005 May;2(2):61-6
references.pmid: 16305060
references.citation: Annu Rev Biochem. 2001;70:341-67
references.pmid: 11395411
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3834-8
references.pmid: 8170997
references.citation: J Med Chem. 2011 Dec 22;54(24):8541-54
references.pmid: 22070604
references.citation: Diabetes. 2007 Nov;56(11):2797-808
references.pmid: 17704298
references.citation: Nature. 1998 Sep 10;395(6698):137-43
references.pmid: 9744270
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1566-71
references.pmid: 10677500
references.citation: Hypertension. 2004 May;43(5):993-1002
references.pmid: 15007034
references.citation: Diabetes Obes Metab. 2007 Jul;9(4):447-54
references.pmid: 17587386
references.citation: J Cell Sci. 2003 May 1;116(Pt 9):1787-96
references.pmid: 12665559
references.citation: Biochim Biophys Acta. 2007 Aug;1771(8):1082-93
references.pmid: 17602866
references.citation: Toxicol Sci. 2014 Apr;138(2):468-81
references.pmid: 24449420
references.citation: Mol Endocrinol. 2006 Apr;20(4):809-30
references.pmid: 16373399
references.citation: Annu Rev Nutr. 2002;22:167-97
references.pmid: 12055342
references.citation: J Clin Endocrinol Metab. 2003 Jun;88(6):2412-21
references.pmid: 12788836
references.citation: Science. 2001 Dec 7;294(5549):2166-70
references.pmid: 11739957
references.citation: Nature. 2011 Sep 22;477(7365):477-81
references.pmid: 21892191
references.citation: Eur J Pharmacol. 2008 Apr 14;584(1):192-201
references.pmid: 18346728
references.citation: Drugs. 2002;62(10):1463-80
references.pmid: 12093315