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Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death

Paola Magnaghi1, Roberto D'Alessio, Barbara Valsasina

  • 1Business Unit Oncology, Nerviano Medical Sciences, Nerviano, Italy.

Nature Chemical Biology
|July 30, 2013
PubMed

Insights

Researchers developed novel compounds targeting VCP (Valosin-containing protein) ATPase, inhibiting its function through covalent or allosteric mechanisms. This discovery validates VCP as a promising target for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Valosin-containing protein (VCP), also known as p97, is a crucial AAA(+) ATPase involved in endoplasmic reticulum-associated degradation.
  • Dysregulation of VCP is implicated in various cellular processes and diseases, including cancer.

Purpose of the Study:

  • To identify and characterize novel VCP inhibitors with distinct mechanisms of action.
  • To validate VCP as a therapeutic target in cancer treatment.

Main Methods:

  • High-throughput screening to identify VCP inhibitors.
  • Photoaffinity labeling, structural analysis, and mutagenesis to map inhibitor binding sites.
  • Biochemical assays to assess VCP enzymatic activity and nucleotide binding.
  • Cell-based assays to evaluate cellular responses and cancer cell death.

Main Results:

  • Developed covalent and allosteric VCP inhibitors.
  • Mapped the allosteric inhibitor binding site to a region spanning D1 and D2 domains, affecting nucleotide sensing and ATP hydrolysis.
  • Identified NMS-873 as a potent and specific VCP inhibitor.
  • Demonstrated that VCP inhibition activates the unfolded protein response, interferes with autophagy, and induces cancer cell death.

Conclusions:

  • VCP is a validated cancer target, with both covalent and allosteric inhibitors demonstrating efficacy in inducing cancer cell death.
  • Novel allosteric inhibitors targeting VCP represent a promising new class of therapeutic agents.

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