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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Gomes, AS (Author) Other; Ramos, H (Author) Other; Gomes, S (Author) Other; Loureiro, JB (Author) Other; Soares, J (Author) Other; Barcherini, V (Author) Other; Monti, P (Author) Other; Fronza, G (Author) Other; Oliveira, C (Author) Other; Domingues, L (Author) Other; Bastos, M (Author) FCUP; Dourado, DFAR (Author) Other; Carvalho, AL (Author) Other; Romao, MJ (Author) Other; Pinheiro, B (Author) Other; Marcelo, F (Author) Other; Carvalho, A (Author) Other; Santos, MMM (Author) Other; Lucilia Saraiva (Author) FFUP

Journal

Title: Biochimica et Biophysica Acta - General Subjects

Vol. 1864

ISSN: 0304-4165

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 12 Citations

Scopus - 12 Citations

Other information

Authenticus ID: P-00R-76V

DOI: 10.1016/j.bbagen.2019.129440

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7