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  3. Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery

Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery

  • Chem Sci. 2020 Jan 21;11(8):2260-2268. doi: 10.1039/c9sc05487a.
Haowen Jiang 1 2,  X Edward Zhou 3,  Jingjing Shi 4,  Zhi Zhou 1,  Guanguan Zhao 4,  Xinwen Zhang 2,  Yili Sun 2,  Kelly Suino-Powell 3,  Lei Ma 1,  Hui Gao 1,  Xiyong Yu 1,  Jia Li 2,  Jingya Li 2,  Karsten Melcher 3,  H Eric Xu 1 4 3,  Wei Yi 1 4
Affiliations

Affiliations

  • 1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology , State Key Laboratory of Respiratory Disease , School of Pharmaceutical Sciences & the Fifth Affiliated Hospital , Guangzhou Medical University , Guangzhou , Guangdong 511436 , China . Email: yiwei@gzhmu.edu.cn.
  • 2 National Center for Drug Screening , State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , Shanghai 201203 , China . Email: jyli@simm.ac.cn ; Email: jli@simm.ac.cn.
  • 3 Structural Biology Program , Center for Cancer and Cell Biology , Van Andel Research Institute , Grand Rapids , Michigan 49503 , USA.
  • 4 VARI/SIMM Center , Center for Structure and Function of Drug Targets , CAS-Key Laboratory of Receptor Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , Shanghai 201203 , China . Email: eric.xu@simm.ac.cn.
PMID: 32190280 DOI: 10.1039/c9sc05487a
Abstract

Peroxisome Proliferator-activated Receptor γ (PPARγ) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARγ-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARγ Modulator (SPPARγM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs.

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