TY - JOUR
T1 - SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations
AU - Gomes, Ana Sara
AU - Ramos, Helena
AU - Gomes, Sara
AU - Loureiro, Joana B.
AU - Soares, Joana
AU - Barcherini, Valentina
AU - Monti, Paola
AU - Fronza, Gilberto
AU - Oliveira, Carla
AU - Domingues, Lucília
AU - Bastos, Margarida
AU - Dourado, Daniel F.A.R.
AU - Carvalho, Ana Luísa
AU - Romão, Maria João
AU - Pinheiro, Benedita
AU - Marcelo, Filipa
AU - Carvalho, Alexandra
AU - Santos, Maria M.M.
AU - Saraiva, Lucília
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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)-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. 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.
AB - 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)-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. 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.
KW - Cancer
KW - Chemotherapy
KW - Mutant
KW - p53
KW - Reactivator
UR - http://www.scopus.com/inward/record.url?scp=85073833530&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073833530&partnerID=8YFLogxK
U2 - 10.1016/j.bbagen.2019.129440
DO - 10.1016/j.bbagen.2019.129440
M3 - Article
C2 - 31536751
AN - SCOPUS:85073833530
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
SN - 0304-4165
M1 - 129440
ER -