9izl
hVanin-1 complexed with X17
Structural highlights
FunctionVNN1_HUMAN Amidohydrolase that hydrolyzes specifically one of the carboamide linkages in D-pantetheine thus recycling pantothenic acid (vitamin B5) and releasing cysteamine.[1] [2] Publication Abstract from PubMedInflammatory bowel disease (IBD) is a clinically heterogeneous disease demanding more therapeutic targets and intervention strategies. Vanin-1, an oxidative stress-regulating protein, has emerged as a promising target for alleviating inflammation and oxidative stress. In this study, a series of thiazole carboxamide derivatives as vanin-1 inhibitors were designed and synthesized. The preferred compound, X17, demonstrated potent inhibition against vanin-1 at the protein, HT-29 cell, and tissue levels, whose binding mode with the target was confirmed via the cocrystal structure. X17 achieved a high bioavailability of 81% in rats, accompanied by concentration-dependent inhibition of serum vanin-1. In a DSS-induced mouse colitis model, X17 exhibited potent anti-inflammatory and antioxidant activities, repressing the inflammatory factor expressions and myeloperoxidase activity, elevating the colonic glutathione reserve, and restoring the intestinal barrier. Collectively, these findings depict the discovery of a potent vanin-1 inhibitor, providing an opportunity for further drug candidate development for treating IBD. Discovery of Thiazole Carboxamides as Novel Vanin-1 Inhibitors for Inflammatory Bowel Disease Treatment.,Xie T, Cao GY, Zhang S, Li MK, Jin X, Liu L, Wang G, Zhen L J Med Chem. 2024 Nov 28;67(22):20372-20398. doi: 10.1021/acs.jmedchem.4c01838. , Epub 2024 Nov 8. PMID:39514323[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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