Discovery of ZG-2305, an Orally Bioavailable Factor Inhibiting HIF Inhibitor for the Treatment of Obesity and Fatty Liver Disease

  • J Med Chem. 2024 Oct 21. doi: 10.1021/acs.jmedchem.4c01698.
Yue Wu  1 ,  Zewei Zhang  1 ,  Haiping Cai  1 ,  Weiqing Zhang  1 ,  Linjian Zhang  1 ,  Zhihong Li  1 ,  Le Yang  1 ,  Yafen Chen  1  2 ,  Thomas P Corner  3 ,  Zhe Song  1 ,  Jie Yue  1 ,  Fulai Yang  1 ,  Xiang Li  1  2 ,  Christopher J Schofield  3 ,  Xiaojin Zhang  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, and Department of Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
PMID: 39432709 DOI: 10.1021/acs.jmedchem.4c01698
Abstract

Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism. FIH is thus a potential target for adiposity control and improving hepatic steatosis. We describe development of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine conformational-flip pocket. ZG-2305, with a Ki of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible factor (HIF) prolyl hydroxylase PHD2. Oral administration of ZG-2305 in the western-diet induced obesity mouse model results in improved lipid accumulation and recovery from abnormal body weight/hepatic steatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related pathological phenotypes in the HF-CDAA-diet induced NASH mouse model was observed. Preliminary preclinical studies indicate ZG-2305 has good pharmacokinetic properties and an acceptable safety profile. The results imply ZG-2305 is a promising candidate for treatment of obesity and fatty liver disease.

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