Discovery of the First‐in‐Class Inhibitors of Hypoxia Up‐Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation

Papadopoulou, Dimitra; Mavrikaki, Vasiliki; Charalampous, Filippos; Tzaferis, Christos; Samiotaki, Martina; Papavasileiou, Konstantinos D.; Afantitis, Antreas; Karagianni, Niki; Denis, Maria C.; Sanchez, Julie; Lane, Robert; Brotzakis, Zacharias Faidon; Skretas, Georgios; Georgiadis, Dimitris; Matralis, Alexios N.; Kollias, George; Papavasileiou, Konstantinos D; Denis, Maria C; Matralis, Alexios N

Abstract

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA-sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast-deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic “hot spots”. Furthermore, we report the discovery of the first-in-class inhibitor leads for hypoxia up-regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.

Citation

Papadopoulou, D., Mavrikaki, V., Charalampous, F., Tzaferis, C., Samiotaki, M., Papavasileiou, K. D., Afantitis, A., Karagianni, N., Denis, M. C., Sanchez, J., Lane, R., Brotzakis, Z. F., Skretas, G., Georgiadis, D., Matralis, A. N., Kollias, G., Papavasileiou, K. D., Denis, M. C., & Matralis, A. N. (2024). Discovery of the First‐in‐Class Inhibitors of Hypoxia Up‐Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation. Angewandte Chemie International Edition, 63(14), Article e202319157. https://doi.org/10.1002/anie.202319157

• Journal Article Type: Article
• Acceptance Date: Feb 9, 2024
• Online Publication Date: Feb 10, 2024
• Publication Date: Apr 2, 2024
• Deposit Date: Mar 7, 2025
• Publicly Available Date: Mar 13, 2025
• Journal: Angewandte Chemie International Edition
• Print ISSN: 1433-7851
• Electronic ISSN: 1521-3773
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 63
• Issue: 14
• Article Number: e202319157
• DOI: https://doi.org/10.1002/anie.202319157
• Keywords: Activated Fibroblasts, Hypoxia Up-regulated Protein 1, Inflammation, Medicinal Chemistry, Small Molecules
• Public URL: https://nottingham-repository.worktribe.com/output/31880174
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/anie.202319157