SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations

Abstract

Background: Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanolderived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. Methods and results: By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. Conclusions: SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. General Significance: This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.

Potency and Selectivity Optimization of Tryptophanol‐Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer

“…This finding was consistent with results obtained recently with compound 1 in cancer cell lines with mutated p53. In these cell lines, compound 1 was shown to activate wt p53 and restore wt‐like function to mutp53 R280 K by directly binding to this protein [42] …”

A selective p53 activator and anticancer agent to improve colorectal cancer therapy

“…Transient transfection of mutp53 in human H1299 tumor cells For ectopic expression of mutp53, p53 null H1299 cells were transfected with 75 ng of pcDNA3 mammalian expression vectors encoding full-length human mutp53 (R280K, R175H, G245D, G245S, R248Q, R248W, R273H, R273C, Y220C or R282W), or empty pcDNA3, as described (Gomes et al, 2020).…”

“…The starting structure for the modeling was the crystal of wtp53 DBD tetramer bound to a DNA target (2AC0) (Kitayner et al, 2006), as described in a previous work (#94) (Gomes et al, 2020). The R248W mutation was performed using Chimera swapaa tool and then geometry optimized with the Amber18/ parm99SB (#100) (Hornak et al, 2006).…”

SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

“…In earlier studies, SLMP53-1 was identified as a new activator of wt-and mutp53, with encouraging in vitro and in vivo p53-dependent antitumor activity [24,27]. Data from SwissADME analysis [25] also showed that SLMP53-1 followed criteria for drug-likeness, gastrointestinal adsorption, lipophilicity, and solubility (Supplementary Tables S1-S7).…”