Author: Appella, Daniel H. ; Robello, Marco ; Jenkins, Lisa M. ; Maity, Tapan K. ; Nikolayevskiy, Herman ; Durell, Stewart R. ; Perciaccante, Andrew J. ; Schilling, Daniel ; Dinan, Jerry C. ; Appella, Ettore ; Lyons, Gaelyn C. ; Tagad, Harichandra D. ; Kumar, Jay P. ; O’Connor, Robert ; Brown, Kate

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.

01 Jun 2024·Cell Biochemistry and Function

Mutant p53 reactivators protect breast cancer cells from ferroptosis

Article

Author: Dlamini, Samkeliso ; Taylor, William R ; Elkalawozgy, Kadry ; Tillekeratne, L M Viranga ; Rathnayake, Dewmi Sandaru

AbstractFerroptosis is a novel nonapoptotic form of cell death characterized by iron‐dependent reactive oxygen species‐mediated lipid peroxidation. In several different cell systems, the tumor suppressor p53 can enhance sensitivity to ferroptotic inducers. At least half of all human cancers show loss of function of p53. Furthermore, many of those tumors express mutant forms of p53 that has lost its wild‐type function. Several groups have designed small molecules that can reactivate the wild‐type function of these missense p53 mutants. We reasoned that p53 reactivators may also enhance sensitivity of certain cancer cells to ferroptosis stimuli. To test this idea we combined a number of different p53 reactivators with small molecule inducers of ferroptosis. In contrast, we observed that several p53 reactivators protected cells from cell death induced by ferroptotic inducers. Surprisingly, this protection still occurred in p53‐null cell lines. We observed that these reactivators were neither free radical scavengers nor ion chelators. One of these p53 reactivator molecules, NSC 59984, reduced expression of GPX4, which is unlikely to explain its ability to reduce sensitivity to ferroptosis. We suggest that these p53 reactivators function via an unknown, p53‐independent manner to suppress ferroptosis.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Preclinical	US	The Fox Chase Cancer Center	15 Sep 2015
Neoplasms	Preclinical	US	Penn State Health	14 Sep 2015

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