2. Academic Validation
  3. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death

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

  • Nat Chem Biol. 2013 Sep;9(9):548-56. doi: 10.1038/nchembio.1313.
Paola Magnaghi 1,  Roberto D'Alessio,  Barbara Valsasina,  Nilla Avanzi,  Simona Rizzi,  Daniela Asa,  Fabio Gasparri,  Liviana Cozzi,  Ulisse Cucchi,  Christian Orrenius,  Paolo Polucci,  Dario Ballinari,  Claudia Perrera,  Antonella Leone,  Giovanni Cervi,  Elena Casale,  Yang Xiao,  Chihunt Wong,  Daniel J Anderson,  Arturo Galvani,  Daniele Donati,  Tom O'Brien,  Peter K Jackson,  Antonella Isacchi
Affiliations

Affiliation

  • 1 Business Unit Oncology, Nerviano Medical Sciences, Nerviano, Italy.
PMID: 23892893 DOI: 10.1038/nchembio.1313
Abstract

VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with Autophagy and induced Cancer cell death. The consistent pattern of Cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a Cancer target.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15713
    99.87%, VCP/p97 抑制剂
    p97
  • HY-15714
    98.05%, p97 抑制剂
    p97
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