journal contribution
posted on 2023-04-04, 00:20 authored by Keelan Z. Guiley, Kevan M. Shokat Supplementary Figure S7: Extended p53 Y220C KG13 cellular activity (A) Western blot for isogenic cell panel treated with 10 μM Nutlin-3a constant or 10 μM KG13 for 1 hr at 28°C, washed out, then moved to 37°C for 8hr. (B) ChIP p53 enrichment for U2OS cells expressing p53 Y220C. (C) p53 ChIP enrichment at CDKN1A and MDM2 promoters relative to IgG following KG13 treatment in H1299 cells expressing p53 Y220C. (D) RT-qPCR results for 25 μM KG13 treated NUGC-4, NUGC-3, and BxPC-3ß cells. (E) Viability assay for KG13 treatment. (F) Viability assay for Nutlin-3a treatment.
Funding
Howard Hughes Medical Institute (HHMI)
Samuel Waxman Cancer Research Foundation (SWCRF)
Emerald Foundation, Inc.
Damon Runyon Cancer Research Foundation (DRCRF)
History
ARTICLE ABSTRACT
The transcription factor and tumor suppressor protein p53 is the most frequently mutated and inactivated gene in cancer. Mutations in p53 result in deregulated cell proliferation and genomic instability, both hallmarks of cancer. There are currently no therapies available that directly target mutant p53 to rescue wild-type function. In this study, we identify covalent compsounds that selectively react with the p53 somatic mutant cysteine Y220C and restore wild-type thermal stability.
The tumor suppressor p53 is the most mutated gene in cancer, and yet no therapeutics to date directly target the mutated protein to rescue wild-type function. In this study, we identify the first allele-specific compound that selectively reacts with the cysteine p53 Y220C to rescue wild-type thermal stability and gene activation.See related commentary by Lane and Verma, p. 14.This article is highlighted in the In This Issue feature, p. 1
