TY - JOUR
T1 - Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule
AU - Soares, Joana
AU - Raimundo, Liliana
AU - Pereira, Nuno A. L.
AU - Monteiro, Ângelo
AU - Gomes, Sara
AU - Bessa, Cláudia
AU - Pereira, Clara
AU - Queiroz, Glória
AU - Bisio, Alessandra
AU - Fernandes, João
AU - Gomes, Célia
AU - Reis, Flávio
AU - Gonçalves, Jorge
AU - Inga, Alberto
AU - Santos, Maria M.M.
AU - Saraiva, Lucília
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016
Y1 - 2016
N2 - 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 transcriptiondependent 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.
AB - 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 transcriptiondependent 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.
KW - Anticancer chemotherapy
KW - Mutant
KW - p53
KW - Tryptophanol-derived oxazoloisoindolinones
KW - Tumor
UR - http://www.scopus.com/inward/record.url?scp=84957991161&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.6775
DO - 10.18632/oncotarget.6775
M3 - Article
C2 - 26735173
AN - SCOPUS:84957991161
SN - 1949-2553
VL - 7
SP - 4326
EP - 4343
JO - Oncotarget
JF - Oncotarget
IS - 4
ER -