2. Academic Validation
  3. Activating p53Y220C with a Mutant-Specific Small Molecule

Activating p53Y220C with a Mutant-Specific Small Molecule

  • bioRxiv. 2024 Oct 28:2024.10.23.619961. doi: 10.1101/2024.10.23.619961.
Xijun Zhu 1 2,  Woong Sub Byun 3 2,  Dominika Ewa Pieńkowska 4,  Kha The Nguyen 5 6,  Jan Gerhartz 4,  Qixiang Geng 3,  Tian Qiu 3,  Jianing Zhong 1,  Zixuan Jiang 1,  Mengxiong Wang 5 6,  Roman C Sarott 3,  Stephen M Hinshaw 3,  Tinghu Zhang 3,  Laura D Attardi 5 6,  Radosław P Nowak 4,  Nathanael S Gray 3
Affiliations

Affiliations

  • 1 Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 2 These authors contributed equally: Xijun Zhu, Woong Sub Byun.
  • 3 Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 4 Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany.
  • 5 Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
  • 6 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
PMID: 39554093 DOI: 10.1101/2024.10.23.619961
Abstract

TP53 is the most commonly mutated gene in Cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 (TRAP-1) due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription. Treatment of p53Y220C expressing pancreatic cell lines with TRAP-1 results in rapid upregulation of p21 and other p53 target genes and inhibits the growth of p53Y220C-expressing cell lines. Negative control compounds that are unable to form a ternary complex do not have these effects, demonstrating the necessity of chemically induced proximity for the observed pharmacology. This approach to activating mutant p53 highlights how chemically induced proximity can be used to restore the functions of tumor suppressor proteins that have been inactivated by mutation in Cancer.

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