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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Activating p53Y220C with a Mutant-Specific Small Molecule.

Xijun Zhu1,2, Woong Sub Byun3,2, Dominika Ewa Pieńkowska4

  • 1Department of Chemistry, Stanford University, Stanford, CA, USA.

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Researchers developed TRanscriptional Activator of p53 (TRAP-1), a novel compound that reactivates the mutated tumor suppressor protein p53. TRAP-1 activates mutant p53, restoring its tumor-suppressing functions and inhibiting cancer cell growth.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The TP53 gene is the most frequently mutated gene in human cancers.
  • Mutant p53 proteins often lose their tumor suppressor functions and are difficult to therapeutically target.
  • Restoring p53 function is a key goal in cancer therapy.

Purpose of the Study:

  • To discover and characterize a small molecule that can reactivate mutant p53.
  • To investigate the mechanism of action for this novel compound.
  • To evaluate the therapeutic potential of reactivating mutant p53 in cancer models.

Main Methods:

  • Discovery of a small molecule chemical inducer of proximity, named TRanscriptional Activator of p53 (TRAP-1).
  • Characterization of TRAP-1's ability to form a ternary complex with mutant p53 and BRD4.
  • Treatment of p53Y220C-expressing pancreatic cancer cell lines with TRAP-1.
  • Analysis of p53 target gene transcription (e.g., p21) and cell growth inhibition.
  • Use of control compounds lacking ternary complex formation capability.

Main Results:

  • TRAP-1 successfully engages mutant p53 and BRD4, forming a ternary complex.
  • This complex formation potently activates mutant p53 and induces robust transcription of p53 target genes.
  • TRAP-1 treatment led to rapid upregulation of p21 and other target genes in p53Y220C-expressing cells.
  • TRAP-1 inhibited the growth of these specific cancer cell lines.
  • Control compounds without ternary complex formation ability did not yield similar results.

Conclusions:

  • Chemically induced proximity is a viable strategy for reactivating mutant tumor suppressor proteins like p53.
  • TRAP-1 demonstrates the potential of this approach to restore lost tumor suppressor functions in cancer.
  • This discovery opens new avenues for developing therapies against cancers with TP53 mutations.