Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1: a novel anticancer small-molecule

TY - JOUR

T1 - Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1

T2 - 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

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 - https://www.scopus.com/pages/publications/84957991161

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 -