Activating p53 Y220C with a Mutant-Specific Small Molecule.

Autor:	Zhu X; Department of Chemistry, Stanford University, Stanford, CA, USA.; These authors contributed equally: Xijun Zhu, Woong Sub Byun., Byun WS; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.; These authors contributed equally: Xijun Zhu, Woong Sub Byun., Pieńkowska DE; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany., Nguyen KT; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Gerhartz J; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany., Geng Q; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA., Qiu T; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA., Zhong J; Department of Chemistry, Stanford University, Stanford, CA, USA., Jiang Z; Department of Chemistry, Stanford University, Stanford, CA, USA., Wang M; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Sarott RC; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA., Hinshaw SM; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA., Zhang T; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA., Attardi LD; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Nowak RP; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany., Gray NS; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 28. Date of Electronic Publication: 2024 Oct 28.
DOI:	10.1101/2024.10.23.619961
Abstrakt:	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 p53 Y220C expressing pancreatic cell lines with TRAP-1 results in rapid upregulation of p21 and other p53 target genes and inhibits the growth of p53 Y220C -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. Competing Interests: Competing interests: All other authors declare no competing interests.
Databáze:	MEDLINE
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