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Choi, Jang Hyun
Lab of Diabetes and Metabolism (LDM)
Research Interests
  • Diabetes, Metabolic Disorders, PPARg, Gene Regulation, Anti-Diabetic Drug


Rational design and synthesis of reversible covalent PPARγ antagonistic ligands inhibiting Ser273 phosphorylation

DC Field Value Language Kim, Hyunsoo ko Jo, Ala ko Choi, Sun-sil ko Nam, Hyunsung ko Byun. Wan Gi ko Bae, Hwan ko Choi, Jang Hyun ko Park, Seung Bum ko 2018-12-21T00:31:53Z - 2018-12-19 ko 2019-09 ko
dc.identifier.citation ASIAN JOURNAL OF ORGANIC CHEMISTRY, v.8, no.9, pp.1698 - 1706 ko
dc.identifier.issn 2193-5807 ko
dc.identifier.uri -
dc.description.abstract Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been a major therapeutic target for the treatment of type 2 diabetes. However, the use of PPAR gamma-targeting drugs such as rosiglitazone and pioglitazone has significantly declined due to adverse effects caused by their classical transcriptional agonism. Meanwhile, blocking the obesity-induced phosphorylation of PPAR gamma at Ser273 by Cdk5 has been proposed as the key to developing insulin-sensitizing effects of PPAR gamma-targeting drugs. In this study, we rationally designed and synthesized selective PPAR gamma phosphorylation inhibitor through a crystal structure-based approach. During this process, we observed a distinct degradation pattern of the anilinic cyanoacrylamide moiety via the spontaneous retro-aldol reaction. Thus, we developed a novel reversible covalent inhibitor of PPAR gamma phosphorylation, SB1495, containing aliphatic cyano-acrylamide, through systematic structural modification, in silico docking studies, time-dependent monitoring of stability in aqueous media, and in vitro kinase assay. We also demonstrated its inhibitory activity on PPAR gamma phosphorylation without classical transactivation in a cellular system as well as in an animal model. ko
dc.language 영어 ko
dc.publisher Wiley - VCH Verlag GmbH & Co. KG ko
dc.title Rational design and synthesis of reversible covalent PPARγ antagonistic ligands inhibiting Ser273 phosphorylation ko
dc.type ARTICLE ko
dc.identifier.scopusid 2-s2.0-85060134757 ko
dc.identifier.wosid 000487092300021 ko
dc.type.rims ART ko
dc.identifier.doi 10.1002/ajoc.201800668 ko
dc.identifier.url ko
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