Page 72 - I. Chemical biology and drug discovery
P. 72
[I. Chemical biology and drug discovery-39]
Development of reversible covalent PPARγ antagonistic
ligands based on a structure-based approach
Hyunsoo Kim¹, Jun Young Jang², Byung Woo Han², Seung Bum Park¹˙*
¹Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea, ²Research Institute of
Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
In this study, we developed a novel reversible covalent PPARγ ligand and demonstrated its antidiabetic activity in
in vitro and in vivo systems. Also, we elucidated the structural basis for the inhibitory effects of a reversible covalent
ligand on PPARγ phosphorylation by X-ray crystallography study. Based on the crystal structure of PPARγ, we
rationally designed and synthesized a series of covalent inhibitor analogues to develop selective PPARγ
phosphorylation inhibitors. As a result, we developed SB1495, novel reversible covalent inhibitor of PPARγ
phosphorylation without classical transactivation. The antidiabetic effect of SB1495 was demonstrated in the cellular
system as well as in the mouse model. We also observed the covalent anchoring of SB1495 on Cys313 at the ligand-
binding pocket of PPARγ by X-ray crystallography.
