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

Yue Wu; Zewei Zhang; Haiping Cai; Weiqing Zhang; Linjian Zhang; Zhihong Li; Le Yang; Yafen Chen; Thomas P Corner; Zhe Song; Jie Yue; Fulai Yang; Xiang Li; Christopher J Schofield; Xiaojin Zhang

doi:10.1021/acs.jmedchem.4c01698

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. Online ahead of print.

Authors

Yue Wu¹, Zewei Zhang¹, Haiping Cai¹, Weiqing Zhang¹, Linjian Zhang¹, Zhihong Li¹, Le Yang¹, Yafen Chen^{1

2}, Thomas P Corner³, Zhe Song¹, Jie Yue¹, Fulai Yang¹, Xiang Li^{1

2}, Christopher J Schofield³, Xiaojin Zhang¹

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 K_i 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.