Research by D. Papadopoulou and V. Mavrikaki in the George Kollias and Alexios Matralis labs, identified first-in-class HYOU1 inhibitors that could be useful for treating chronic inflammation and fibrosis.
Dimitra Papadopoulou and Vasiliki Mavrikaki, et al., at George Kollias and Alexios Matralis laboratories recently published in ‘Angewandte Chemie’ an article titled “Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation”. The study describes a multidisciplinary “hit to lead” approach that identified novel small molecule inhibitors of pathogenic activation of fibroblasts, as seen in inflammation and fibrosis.
This work combined medicinal chemistry, molecular phenotyping, chemoproteomics, bulk RNA-sequencing analysis and target validation experiments with ADMET/pharmacokinetic (PK) and in vivo evaluation of the novel bioactive small molecules. Importantly, HYOU1, a member of the heat shock protein 70 (HSP70) family, was identified as the primary molecular target of the new derivatives, thus rendering them the first-in-class HYOU1 inhibitors. The new compound series decreased various pathogenic fibroblast activation properties, such as their inflammatory secretome, wound healing potential and ECM-related gene expression. The latter was accompanied by a potent anti-inflammatory effect of the compounds in vivo, effectively mitigating acute lipopolysaccharide (LPS)-mediated endotoxemia in mice.
Conclusively, the study shows that targeting HYOU1 with novel inhibitors may represent a novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.
Publication: Papadopoulou D, Mavrikaki V, Charalampous F, Tzaferis C, Samiotaki M, Papavasileiou KD, Afantitis A, Karagianni N, Denis MC, Sanchez J, Lane JR, Faidon Brotzakis Z, Skretas G, Georgiadis D, Matralis AN, Kollias G. Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation. Angew Chem Int Ed Engl. 2024 Apr 2;63(14):e202319157. doi: 10.1002/anie.202319157. Epub 2024 Feb 26. PMID: 38339863.
https://doi.org/10.1002/anie.202319157
