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Hsp70 and the Unfolded Protein Response as a Challenging Drug Target and an Inspiration for Probe Molecule

Leila Terrab1, Peter Wipf1

  • 1Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

ACS Medicinal Chemistry Letters
|March 19, 2020
PubMed

Insights

Modulating Hsp70 ATPase activity impacts the unfolded protein response (UPR). This dual action can induce cancer cell death or promote neuronal survival, offering therapeutic potential for various diseases.

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Pharmacology

Background:

  • The unfolded protein response (UPR) is a critical cellular mechanism for maintaining protein homeostasis and cell survival under stress.
  • Hsp70 chaperone's ATPase activity plays a key role in regulating the UPR.
  • Dysregulation of protein homeostasis is implicated in various diseases, including cancer, neurodegeneration, and aging.

Purpose of the Study:

  • To explore the complex protein homeostasis network and its regulation by Hsp70.
  • To discuss strategies for modulating Hsp70 ATPase activity for therapeutic benefit.
  • To highlight the dual role of Hsp70 modulation in UPR-mediated cell fate.

Main Methods:

  • Review of existing literature on UPR and Hsp70.
  • Discussion of pharmacological approaches targeting Hsp70 ATPase activity.
  • Introduction of a chemical reaction development-inspired library of Hsp70 modulators.

Main Results:

  • Pharmacological modulation of Hsp70 ATPase activity can selectively trigger UPR-mediated cell death in cancer cells.
  • Alternatively, Hsp70 modulation can promote cell survival, preventing apoptosis in neuronal cells.
  • This dual effect suggests potential applications in treating malignancies, neurodegenerative diseases, and inflammatory conditions.

Conclusions:

  • Hsp70 modulation represents a promising therapeutic strategy with context-dependent outcomes.
  • Targeting Hsp70 offers a novel approach to managing diseases associated with protein misfolding and cellular stress.
  • Further research into Hsp70 modulators could lead to significant advancements in medicine.

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