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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 1; p. 129440
• Main Authors: Gomes, Ana Sara, Ramos, Helena, Gomes, Sara, Loureiro, Joana B., Soares, Joana, Barcherini, Valentina, Monti, Paola, Fronza, Gilberto, Oliveira, Carla, Domingues, Lucília, Bastos, Margarida, Dourado, Daniel F.A.R., Carvalho, Ana Luísa, Romão, Maria João, Pinheiro, Benedita, Marcelo, Filipa, Carvalho, Alexandra, Santos, Maria M.M., Saraiva, Lucília
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2020
• Subjects: antineoplastic activity; Cancer; chemical interactions; Chemotherapy; DNA; DNA-binding domains; humans; Mutant; mutants; mutation; neoplasm cells; neoplasms; p53; patients; proteins; Reactivator; therapeutics; thermal stability; yeasts; CETSA; Chemotherapy; SRB; mutp53; Mutant; DBD; Reactivator; wt; p53; Cancer
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.129440

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)-tryptophanol-derived 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. 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. SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status. [Display omitted] •SLMP53-1 binds to wild-type and mutant p53 R280K DNA-binding domain.•SLMP53-1 reactivates multiple hotspot mutant p53.•In silico, SLMP53-1 bridges the interface of the p53 homodimer with the DNA.•SLMP53-1 brings new insights into p53 druggability.•SLMP53-1 reveals encouraging application in personalized cancer treatment.