Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Proteinâ
1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.
Angew Chem Int Ed Engl
; 63(14): e202319157, 2024 04 02.
Article
em En
| MEDLINE
| ID: mdl-38339863
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)â
pinpoint key structural elements of the scaffold that provide potent fibroblast-deactivating effects in cells, b)â
discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c)â
identify metabolic "hot spots". Furthermore, we report the discovery of the first-in-class inhibitor leads for hypoxia up-regulated proteinâ
1 (HYOU1), a member of the heat shock proteinâ
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.
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Base de dados:
MEDLINE
Assunto principal:
Fibroblastos
/
Inflamação
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article