In tissues after a prolonged injury or a chronic inflammation the persistence of repair processes leads to the aberrant extracellular matrix (ECM) deposition (i.e. tissue fibrosis). Fibrosis ultimately compromise the function(s) of the organ resulting in diseases (i.e. idiopathic pulmonary fibrosis, liver cirrhosis, or renal fibrosis, etc) responsible of several thousands of deaths per year. The massive ECM deposition is mediated by excessive/persistent release of pro-inflammatory cytokines and growth factors that stimulates myofibroblasts expansion, de-regulates metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. To date the pharmacological care in patients with tissue fibrosis relies on corticosteroids and immunosuppressant drugs and it is rather unsatisfactory since often the ultimate resource is an organ transplant. Modern pharmacological strategies aim to take inhibiting specific components of the fibrogenic pathways by mean of monoclonal antibodies or small molecules. Along this line, mTOR, a serine/threonine kinase belonging to the family of phosphoinositide 3-kinase related kinases, has emerged as a potential target for anti-fibrotic therapies. Herein we report the discovery of novel quinazolinone based mTOR inhibitors that showed interesting antifibrotic properties while not showing cytotoxic activities. The title compounds have been identified starting from the screening of an in-house library of properly designed potential kinase inhibitors. Those compounds that showed to be selective mTOR inhibitors have been then submitted to cytotoxic experiments. The molecules unable to impair cell viability have been then submitted to specific assays in order to investigate the antifibrotic properties. In particular, the selected molecules (at 1 µM) reduced the fibrosis-related mRNA transcript levels (i.e. collagen type I and fibronectin) in primary human hepatic stellate cells and intestinal myofibroblasts, two different cellular populations involved in the fibrogenic process of liver and gut, respectively. Finally, molecular modelling studies (based on an homology model of mTOR kinase) have been used to propose a plausible binding mode for quinazolinone compounds.

Discovery of Novel Quinazolinone Based mTOR Inhibitors Endowed with Antifibrotic Properties

MARZARO, GIOVANNI;BRUN, PAOLA;CASTAGLIUOLO, IGNAZIO;FERRARESE, ALESSANDRO;MANZINI, PAOLO;CHILIN, ADRIANA
2013

Abstract

In tissues after a prolonged injury or a chronic inflammation the persistence of repair processes leads to the aberrant extracellular matrix (ECM) deposition (i.e. tissue fibrosis). Fibrosis ultimately compromise the function(s) of the organ resulting in diseases (i.e. idiopathic pulmonary fibrosis, liver cirrhosis, or renal fibrosis, etc) responsible of several thousands of deaths per year. The massive ECM deposition is mediated by excessive/persistent release of pro-inflammatory cytokines and growth factors that stimulates myofibroblasts expansion, de-regulates metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. To date the pharmacological care in patients with tissue fibrosis relies on corticosteroids and immunosuppressant drugs and it is rather unsatisfactory since often the ultimate resource is an organ transplant. Modern pharmacological strategies aim to take inhibiting specific components of the fibrogenic pathways by mean of monoclonal antibodies or small molecules. Along this line, mTOR, a serine/threonine kinase belonging to the family of phosphoinositide 3-kinase related kinases, has emerged as a potential target for anti-fibrotic therapies. Herein we report the discovery of novel quinazolinone based mTOR inhibitors that showed interesting antifibrotic properties while not showing cytotoxic activities. The title compounds have been identified starting from the screening of an in-house library of properly designed potential kinase inhibitors. Those compounds that showed to be selective mTOR inhibitors have been then submitted to cytotoxic experiments. The molecules unable to impair cell viability have been then submitted to specific assays in order to investigate the antifibrotic properties. In particular, the selected molecules (at 1 µM) reduced the fibrosis-related mRNA transcript levels (i.e. collagen type I and fibronectin) in primary human hepatic stellate cells and intestinal myofibroblasts, two different cellular populations involved in the fibrogenic process of liver and gut, respectively. Finally, molecular modelling studies (based on an homology model of mTOR kinase) have been used to propose a plausible binding mode for quinazolinone compounds.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3018500
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact