Hsp90 (i.e., Heat shock protein 90) is a well-established therapeutic target for several diseases, ranging from misfolding-related disfunctions to cancer. In this framework, we have developed in recent years a family of benzofuran compounds that act as Hsp90 allosteric modulators. Such molecules can interfere with the stability of some relevant Hsp90 client oncoproteins, showing a low μM cytotoxic activity in vitro in cancer cell lines. Here we identify the target profile of these chemical probes by means of chemical proteomics, which established MDH2 (mitochondrial malate dehydrogenase) as an additional relevant cellular target that might help elucidate the molecular mechanism of their citotoxicity. Western blotting, DARTS (i.e., Drug Affinity Responsive Target Stability) and enzymatic assays data confirmed a dose-dependent interaction of MDH2 with several members of the benzofuran Hsp90 modulators family and a computational model allowed to interpret the observed interactions.

Analysis of Hsp90 allosteric modulators interactome reveals a potential dual action mode involving mitochondrial MDH2 / C. Cassiano, E. Morretta, M. Costantini, E.M.A. Fassi, G. Colombo, S. Sattin, A. Casapullo. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - 115(2021 Oct), pp. 105258.1-105258.8. [10.1016/j.bioorg.2021.105258]

Analysis of Hsp90 allosteric modulators interactome reveals a potential dual action mode involving mitochondrial MDH2

Fassi E. M. A.;Sattin S.;
2021-10

Abstract

Hsp90 (i.e., Heat shock protein 90) is a well-established therapeutic target for several diseases, ranging from misfolding-related disfunctions to cancer. In this framework, we have developed in recent years a family of benzofuran compounds that act as Hsp90 allosteric modulators. Such molecules can interfere with the stability of some relevant Hsp90 client oncoproteins, showing a low μM cytotoxic activity in vitro in cancer cell lines. Here we identify the target profile of these chemical probes by means of chemical proteomics, which established MDH2 (mitochondrial malate dehydrogenase) as an additional relevant cellular target that might help elucidate the molecular mechanism of their citotoxicity. Western blotting, DARTS (i.e., Drug Affinity Responsive Target Stability) and enzymatic assays data confirmed a dose-dependent interaction of MDH2 with several members of the benzofuran Hsp90 modulators family and a computational model allowed to interpret the observed interactions.
Benzofurans; Chemical proteomics; Docking; Hsp90; Mitochondrial malate dehydrogenase; Allosteric Regulation; Antineoplastic Agents; Benzofurans; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins; Humans; Malate Dehydrogenase; Models, Molecular; Molecular Structure; Structure-Activity Relationship
Settore CHIM/06 - Chimica Organica
12-ago-2021
Article (author)
File in questo prodotto:
File Dimensione Formato  
Cassiano et al_author accepted manuscript_AIR.pdf

embargo fino al 12/08/2023

Descrizione: accepted manuscript
Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 1 MB
Formato Adobe PDF
1 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
S0045206821006350.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 2.26 MB
Formato Adobe PDF
2.26 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
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/2434/907494
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact