A Small‐Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine‐Flip Pocket for the Treatment of Obesity

Author:

Wu Yue1,Chen Yafen1,Corner Thomas P.2,Nakashima Yu23,Salah Eidarus2,Li Zhihong1,Zhang Linjian1,Yang Le1,Tumber Anthony2,Sun Zhuoli1,Wen Yukang1,Zhong Ailin1,Yang Fulai1,Li Xiang1,Zhang Zhihong2,Schofield Christopher J.2ORCID,Zhang Xiaojin1

Affiliation:

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. Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research University of Oxford 12 Mansfield Road Oxford OX1 3TA United Kingdom

3. Present address: Institute of Natural Medicine University of Toyama 2630-Sugitani 930-0194 Toyama Japan.

Abstract

AbstractIn animals, limiting oxygen upregulates the hypoxia‐inducible factor (HIF) and promotes a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs) which, like FIH, are 2‐oxoglutarate (2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non‐HIF substrates making it challenging to connect its biochemistry with physiology. A structure–mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG‐2291, the binding of which promotes a conformational flip of a catalytically important tyrosine, enabling the selective inhibition of FIH over other Jumonji C subfamily 2OG oxygenases. Consistent with genetic studies, ZG‐2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG‐2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.

Funder

National Natural Science Foundation of China

Science Fund for Distinguished Young Scholars of Jiangsu Province

Wellcome Trust

Publisher

Wiley

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