Identification of a Small Molecule That Overcomes HdmX-Mediated Suppression of p53.
Mol Cancer Ther
; 15(4): 574-582, 2016 04.
Article
em En
| MEDLINE
| ID: mdl-26883273
ABSTRACT
Inactivation of the p53 tumor suppressor by mutation or overexpression of negative regulators occurs frequently in cancer. As p53 plays a key role in regulating proliferation or apoptosis in response to DNA-damaging chemotherapies, strategies aimed at reactivating p53 are increasingly being sought. Strategies to reactivate wild-type p53 include the use of small molecules capable of releasing wild-type p53 from key, cellular negative regulators, such as Hdm2 and HdmX. Derivatives of the Hdm2 antagonist Nutlin-3 are in clinical trials. However, Nutlin-3 specifically disrupts Hdm2-p53, leaving tumors harboring high levels of HdmX resistant to Nutlin-3 treatment. Here, we identify CTX1, a novel small molecule that overcomes HdmX-mediated p53 repression. CTX1 binds directly to HdmX to prevent p53-HdmX complex formation, resulting in the rapid induction of p53 in a DNA damage-independent manner. Treatment of a panel of cancer cells with CTX1 induced apoptosis or suppressed proliferation and, importantly, CTX1 demonstrates promising activity as a single agent in a mouse model of circulating primary human leukemia. CTX1 is a small molecule HdmX inhibitor that demonstrates promise as a cancer therapeutic candidate. Mol Cancer Ther; 15(4); 574-82. ©2016 AACR.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Proteína Supressora de Tumor p53
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Proteínas Proto-Oncogênicas
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Descoberta de Drogas
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Antineoplásicos
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article