Recently, Prof. Xiaojin Zhang's team from the College of Science of our university published the latest research results entitled “A small-molecule inhibitor of factor inhibiting A small-molecule inhibitor of factor inhibiting HIF binding to a tyrosine-flip pocket for the treatment of obesity” was published in the prestigious international journal Angewandte Chemie International Edition (IF:16.1), and was selected as a highlight of the back cover article. Prof. Xiaojin Zhang from China Pharmaceutical University (CPU) and Prof. Christopher J. Schofield from Department of Chemistry, University of Oxford are the corresponding authors of this article, and Postdoctoral Fellow Yue Wu, a PhD graduate from the class of 2024, is the first author of this article, and CPU is the first corresponding author of this article.
Obesity has become a growing health problem worldwide. Although GLP-1 receptor agonists have shown significant efficacy in the treatment of obesity, they still suffer from appetite suppression, rebound after discontinuation and muscle loss. Therefore, there is an urgent need to develop new therapeutic tools for this complex condition. The cellular oxygen receptor, hypoxia-inducible factor (HIF) inhibitor (factor inhibiting HIF, FIH), is a Fe(II)/2OG-dependent dioxygenase of the JmjC family that catalyzes the hydroxylation of specific asparagine residues of substrate proteins, such as HIF-α, to negatively regulate the HIF transcriptional activity. Studies have shown that FIH has an important regulatory role in cellular energy metabolism and lipid metabolism, and FIH knockdown can protect against high-fat diet-induced obesity and fatty liver. However, due to the relatively narrow 2OG binding pocket of FIH, the development of small molecule inhibitors of FIH faces great challenges.
Prof. Xiaojin Zhang's team obtained novel FIH inhibitors by SPE-MS screening, and used structural biology techniques to discover a brand new pocket formed by ligand binding-induced conformational flip of the Tyr102 side chain (Tyr102-flip pocket), which lays a structural foundation for the development of selective FIH inhibitors. Through structural optimization, the researchers obtained ZG-2291, an effective selective FIH small molecule inhibitor in vivo, which induces a conformational flip of Tyr102 and occupies both the 2OG pocket and the Tyr102-flip pocket, and this unique mode of action enables ZG-2291 to exhibit high FIH inhibitory activity and selectivity for other Fe(II)/2OG oxygenases.ZG-2291 can inhibit FIH through the inhibition of FIH. 2291 can inhibit FIH, specifically activate the EGLN3 gene downstream of HIF, and activate the PPARα/γ - PCG-1α pathway to up-regulate the expression of obesity and lipid metabolism related genes, such as UCP1, to significantly reduce the body weight of ob/ob mice without affecting the dietary intake, and also show a significant improvement in the metabolism related disorders. In addition, Prof. Zhang's team also carried out further structural optimization and comprehensive preclinical studies on ZG-2291, and successfully obtained a preclinical candidate compound (PCC) for FIH inhibition. The candidate compound has shown anti-obesity efficacy comparable to the marketed drug Simeglutide and anti-NAFLD/NASH efficacy comparable to Resmetirom at a dose of 10 mpk orally, with good pharmacokinetic properties and safety, which provides a potential new target candidate molecule for the treatment of fat metabolic diseases, such as obesity, NAFLD/NASH, and so on.
Figure: Chemical structure of ZG-2291, a small molecule inhibitor of FIH, and its binding mode to the target.
This research work was supported by the National Natural Science Foundation of China (NSFC) Outstanding Youth Fund Program, NSFC Facet Program, Jiangsu Province Outstanding Youth Fund, Xing Pharmaceutical Scholar Program of China Pharmaceutical University, and Jiangsu Province Key Laboratory of Pharmaceutical Molecular Design and Optimization of Drug-forming Properties.
Article link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202410438
