Allosteric Modulators of HSP90 and HSP70

Dynamics Meets Function through Structure-Based Drug Design

Mariarosaria Ferraro, Ilda D'Annessa, Elisabetta Moroni, Giulia Morra, Antonella Paladino, Silvia Rinaldi, Federica Compostella, Giorgio Colombo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Molecular chaperones HSP90 and HSP70 are essential regulators of the folding and activation of a disparate ensemble of client proteins. They function through ATP hydrolysis and the assembly of multiprotein complexes with cochaperones and clients. While their therapeutic relevance is recognized, important details underlying the links between ATP-dependent conformational dynamics and clients/cochaperones recruitment remain elusive. Allosteric modulators represent fundamental tools to obtain molecular insights into functional regulation. By selective perturbation of different aspects of HSP90/HSP70 activities, allosteric drugs can tune rather than completely inhibit signaling cascades, providing information on the relationships between structure-dynamics and function. Herein, we review advances in the design of HSP90 and HSP70 allosteric modulators. We consider inhibitors and activators in different biochemical and disease models. We discuss these compounds as probes to decipher the complexity of the chaperone machinery and that at the same time represent starting leads for the development of drugs against cancer and neurodegeneration.

Original languageEnglish
Pages (from-to)60-87
Number of pages28
JournalJournal of Medicinal Chemistry
Volume62
Issue number1
DOIs
Publication statusPublished - Oct 1 2019

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Drug Design
Adenosine Triphosphate
Multiprotein Complexes
Molecular Chaperones
Pharmaceutical Preparations
Hydrolysis
Neoplasms
Proteins
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Allosteric Modulators of HSP90 and HSP70 : Dynamics Meets Function through Structure-Based Drug Design. / Ferraro, Mariarosaria; D'Annessa, Ilda; Moroni, Elisabetta; Morra, Giulia; Paladino, Antonella; Rinaldi, Silvia; Compostella, Federica; Colombo, Giorgio.

In: Journal of Medicinal Chemistry, Vol. 62, No. 1, 01.10.2019, p. 60-87.

Research output: Contribution to journalArticle

Ferraro, Mariarosaria ; D'Annessa, Ilda ; Moroni, Elisabetta ; Morra, Giulia ; Paladino, Antonella ; Rinaldi, Silvia ; Compostella, Federica ; Colombo, Giorgio. / Allosteric Modulators of HSP90 and HSP70 : Dynamics Meets Function through Structure-Based Drug Design. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 1. pp. 60-87.
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