Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation
Δημιουργός/Συγγραφέας:	Papadopoulou, Dimitra Mavrikaki, Vasiliki Charalampous, Filippos Tzaferis, Christos Samiotaki, Martina Papavasileiou, Konstantinos D Afantitis, Antreas Karagianni, Niki Denis, Maria C Sanchez, Julie Lane, J Robert Faidon Brotzakis, Zacharias [EL] Σκρέτας, Γιώργος[EN] Skretas, George Georgiadis, Dimitris Matralis, Alexios N Kollias, George
Ημερομηνία:	2024-04-02
ISSN:	1433-7851 1521-3773
DOI:	10.1002/anie.202319157
Άλλο:	38339863
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	Angewandte Chemie (International ed. in English)
Τόμος/Κεφάλαιο:	63
Τεύχος:	14
Θεματική Κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry [EL] Μοριακή Βιολογία[EN] Molecular Biology [EL] Παθολογία[EN] Pathology [EL] Κυτταρολογία[EN] Cytology [EL] Νεοπλάσματα. Όγκοι. Ογκολογία (περ. Καρκίνος, κακινογόνες ουσίες)[EN] Neoplasms. Tumors. Oncology (Incl.cancer, carcinogens)
Λέξεις-Κλειδιά:	activated fibroblasts hypoxia up-regulated protein 1 inflammation medicinal chemistry small molecules
Χρηματοδότης:	General Secretariat for Research and Technology (GSRT) Stavros Niarchos Foundation European Research Council
EU Grant identifier:	Τ2ΕDΚ-01076 MIS 5002135 MIS 5002802 101055093
Κάτοχος πνευματικών δικαιωμάτων:	© 2024 The Authors
Όροι και προϋποθέσεις δικαιωμάτων:	This is an open access article under the terms of the Creative Commons Attribution Non Commercial No Derivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1002/anie.202319157
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο