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Novel anti-cancer compounds: structure-based discovery of chemical chaperons for p53

Yumiko Okuda1, Hironori K Nakamura, Kazuo Kuwata

  • 1Division of Prion Research, Center for Emerging Infectious Diseases, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.

Oncology Reports
|September 3, 2009
PubMed

Insights

Researchers identified chemical chaperones to stabilize the tumor suppressor protein p53, restoring its anti-cancer activity. Two compounds, GJC29 and GJC30, showed significant efficacy in inhibiting cancer cell proliferation in vitro and in vivo.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 is vital for preventing cancer proliferation.
  • Mutations destabilizing p53 disrupt its DNA binding and anti-cancer functions.
  • Restoring functional p53 conformation is a key strategy for cancer treatment.

Purpose of the Study:

  • To discover small compounds, termed 'chemical chaperones', that stabilize functional p53 conformation.
  • To restore the anti-cancer activity of destabilized p53.

Main Methods:

  • Docking simulations using AutoDock and the ZINC database to identify potential compounds.
  • In vitro anti-cancer activity assessment using MTT assays on HCT116 colon cancer cells.
  • Surface Plasmon Resonance (SPR) measurements to confirm p53-compound interactions.
  • In vivo efficacy testing in nude mice bearing HCT116 tumors.

Main Results:

  • 70 compounds (GJC1-GJC70) were initially selected based on docking energy.
  • Compounds GJC29 and GJC30 demonstrated significant inhibition of cancer cell proliferation, outperforming the positive control staurosporine.
  • SPR confirmed the interaction between p53 and the novel compounds.
  • GJC29 exhibited a strong suppressive effect on cancer proliferation in vivo.

Conclusions:

  • p53 is a viable target for the rational design of chemical chaperones for cancer therapy.
  • GJC29 and GJC30 represent promising candidates for further development as anti-cancer agents.
  • Chemical chaperones offer a novel therapeutic approach to restore tumor suppressor function.

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