Covalent Modification of p53 by ( E )-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one.

Autor:	Brown K; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Robello M; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20814, United States., Perciaccante AJ; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Dinan JC; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Maity TK; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Lyons GC; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Kumar JP; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Durell SR; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Tagad HD; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Schilling D; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Nikolayevskiy H; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20814, United States., O'Connor R; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20814, United States., Appella E; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States., Appella DH; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20814, United States., Jenkins LM; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Oct 14; Vol. 7 (11), pp. 3559-3572. Date of Electronic Publication: 2024 Oct 14 (Print Publication: 2024).
DOI:	10.1021/acsptsci.4c00447
Abstrakt:	TP53 is commonly mutated in cancer, giving rise to loss of wild-type tumor suppressor function and increases in gain-of-function oncogenic roles. Thus, inhibition of mutant p53 and reactivation of wild-type function represents a potential means to target diverse tumor types. ( E )-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984), first identified from a high-throughput screen, induces wild-type p53 signaling and antiproliferative effects while inhibiting mutant p53 gain-of-function activities. Here, we investigate the specific mechanism of action of NSC59984 against p53. We found that NSC59984 reacts with thiols via an unusual Michael addition at the α-carbon. Covalent modification of p53 Cys124 and Cys229 was observed both following in vitro reaction and upon treatment of cells. Finally, we used a biotinylated form of NSC59984 and, separately, thermal proteome profiling to examine off-target effects, identifying several metabolic proteins involved in cellular metabolism as potential targets. These results demonstrate that covalent modification of p53 by NSC59984 leads to increased wild-type activity and suggest that potential reaction with metabolic enzymes may contribute to antiproliferative function. Competing Interests: The authors declare no competing financial interest. (Not subject to U.S. Copyright. Published 2024 by American Chemical Society.)
Databáze:	MEDLINE
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