2. Academic Validation
  3. Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation

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

  • Angew Chem Int Ed Engl. 2024 Feb 10:e202319157. doi: 10.1002/anie.202319157.
Dimitra Papadopoulou 1,  Vasiliki Mavrikaki 2 3,  Filippos Charalampous 1,  Christos Tzaferis 1,  Martina Samiotaki 1,  Konstantinos D Papavasileiou 4 5 6,  Antreas Afantitis 4 5 6,  Niki Karagianni 7,  Maria C Denis 7,  Julie Sanchez 8 9,  J Robert Lane 8 9,  Zacharias Faidon Brotzakis 10 1,  Georgios Skretas 1 11,  Dimitris Georgiadis 3,  Alexios N Matralis 1,  George Kollias 1 12 13
Affiliations

Affiliations

  • 1 Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", 16672, Vari, Greece.
  • 2 Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", Vari, 16672, Athens, Greece.
  • 3 Department of Chemistry, Laboratory of Organic Chemistry, National and Kapodistrian University of Athens, 15784, Athens, Greece.
  • 4 Department of ChemoInformatics, Novamechanics Ltd., 1070, Nicosia, Cyprus.
  • 5 Department of Chemoinformatics, Novamechanics MIKE, 18545, Piraeus, Greece.
  • 6 Division of Data Driven Innovation, Entelos Institute, 6059, Larnaca, Cyprus.
  • 7 Biomedcode Hellas S.A., 16672, Vari, Greece.
  • 8 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, NG7 2UH, Nottingham, U.K.
  • 9 Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, NG2 7AG, Midlands, U.K.
  • 10 Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, U.K.
  • 11 Institute of Chemical Biology, National Hellenic Research Foundation, 11635, Athens, Greece.
  • 12 Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
  • 13 Research Institute of New Biotechnologies and Precision Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece.
PMID: 38339863 DOI: 10.1002/anie.202319157
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.

Keywords

Activated fibroblasts; Hypoxia up-regulated protein 1; Inflammation; Medicinal chemistry; Small molecules.

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