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

Bioorg Chem. 2021 Oct:115:105258. doi: 10.1016/j.bioorg.2021.105258. Epub 2021 Aug 9.

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.

Keywords: Benzofurans; Chemical proteomics; Docking; Hsp90; Mitochondrial malate dehydrogenase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Dose-Response Relationship, Drug
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Malate Dehydrogenase / antagonists & inhibitors*
  • Malate Dehydrogenase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzofurans
  • HSP90 Heat-Shock Proteins
  • MDH2 protein, human
  • Malate Dehydrogenase
  • benzofuran