Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy

Related Experiment Video

Updated: Dec 26, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

11.0K

Feng Wang1,2, Shan Li1,2, Taiping Gan1

  • 1Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and The Lundquist Institute, Torrance, CA, 90502, USA.

Chemmedchem
|March 13, 2020
PubMed

Insights

Drug resistance in cancer therapy is a major challenge. Allosteric p97 inhibitors show promise against resistant cancer cells, offering an alternative to ATP-competitive inhibitors like CB-5083.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted cancer therapies face challenges due to drug-resistant mutations.
  • p97/VCP is a crucial protein homeostasis regulator and a promising anticancer target.
  • ATP-competitive p97 inhibitor CB-5083 is in clinical trials, but resistance can emerge.

Purpose of the Study:

  • To identify alternative p97 inhibitors effective against drug-resistant cancer mutations.
  • To evaluate the efficacy of allosteric p97 inhibitors in overcoming resistance to ATP-competitive inhibitors.

Main Methods:

  • Generation of CB-5083 resistant HCT116 cell lines with specific p97 mutations (N660K, T688A, D649A/T688A).
  • Assessment of sensitivity of resistant mutants to various ATP-competitive and allosteric p97 inhibitors.
  • Comparative analysis of inhibitor potency against parental and resistant cell lines.

Main Results:

  • Two CB-5083 resistant mutants (N660K, T688A) showed cross-resistance to other ATP-competitive p97 inhibitors.
  • Allosteric inhibitors (NMS-873, UPCDC-30245) were effective against these resistant mutants.
  • A double mutant (D649A/T688A) was significantly more sensitive to allosteric inhibitors than CB-5083.

Conclusions:

  • Allosteric p97 inhibitors represent a viable strategy to overcome resistance developed against ATP-competitive p97 inhibitors.
  • This finding offers potential for improved cancer treatment outcomes in the face of acquired drug resistance.
Keywords:
ATPasebiological activitycancerp97 VCPresistancesmall-molecule inhibitors

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