Abstract
Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53-reactivating drugs.
Highlights
The p53 transcription factor finely regulates the expression of genes with central roles in cellular processes including DNA repair, cell cycle, and apoptosis [1, 2]
50 μM PhiKan083 restored the wt p53-induced growth inhibition to mut p53Y220C. This yeast assay was thereafter used to evaluate the effect of synthesized enantiopure tryptophanol-derived oxazoloisoindolinones on wt and mut p53 activity
These compounds were synthesized following our interest in enantiopure biologically active amino alcohol-derived compounds [10,11,12], and on our previous discovery of phenylalaninol-derived oxazoloisoindolinones with in vitro p53-dependent antitumor activity [10]
Summary
The p53 transcription factor finely regulates the expression of genes with central roles in cellular processes including DNA repair, cell cycle, and apoptosis [1, 2]. The majority of p53 mutations are missense, preferentially localized in the DNA binding domain They can be classified as structural (e.g., R175H, Y220C) or DNA contact (e.g., R273H, R280K) based on whether or not they lead to a profound protein conformational change, respectively. High levels of mutant (mut) p53 are often found in tumors due to a reduced MDM2 expression, and consequent impairment of p53 degradation [3]. These observations support that mut p53 is a promising therapeutic target against a wide range of aggressive tumors [3,4,5]
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