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NMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells

Shan Li1, Feng Wang1, Gang Zhang1

  • 1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Pharmaceutics
|April 23, 2022
PubMed

Insights

Allosteric inhibitor NMS-873 targets glycometabolism independently of p97, offering a new strategy against colon cancer drug resistance. This polypharmacology enhances anti-cancer therapy effectiveness.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Adenosine triphosphate (ATP)-competitive p97 inhibitors like CB-5083 show promise in anti-cancer therapy.
  • Drug-induced resistance is a major challenge in targeted cancer therapy.
  • Allosteric inhibitors offer a potential strategy to overcome resistance.

Purpose of the Study:

  • To investigate the mechanism of action of allosteric p97 inhibitor NMS-873.
  • To identify drug targets and off-target effects of NMS-873.
  • To explore the potential of NMS-873 in overcoming drug resistance in colon cancer.

Main Methods:

  • Chemical proteomics and drug-induced thermal proteome changes (PISA T) were used to identify drug targets.
  • Drug-resistant cell lines were established and analyzed.
  • Cell-based assays and proteomic analysis were performed.

Main Results:

  • NMS-873, unlike CB-5083, was found to affect glycometabolism.
  • NMS-873 dysregulates glycometabolism in a p97-independent manner.
  • NDUFAF5 in mitochondrial complex I was identified as a potential target of NMS-873.
  • The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) enhanced the anti-proliferative effect of NMS-873.

Conclusions:

  • NMS-873 exhibits polypharmacology, impacting glycometabolism independently of p97.
  • This distinct mechanism suggests NMS-873's potential for overcoming drug resistance in colon cancer.
  • The combination of NMS-873 with glycolysis inhibitors may enhance anti-cancer therapy efficacy.
Keywords:
glycometabolismp97 inhibitorprotein stabilityproteomicsresistance

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