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Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors.

Authors :
Issaeva N
Bozko P
Enge M
Protopopova M
Verhoef LG
Masucci M
Pramanik A
Selivanova G
Source :
Nature medicine [Nat Med] 2004 Dec; Vol. 10 (12), pp. 1321-8. Date of Electronic Publication: 2004 Nov 21.
Publication Year :
2004

Abstract

In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation. We have screened a chemical library and identified a small molecule named RITA (reactivation of p53 and induction of tumor cell apoptosis), which bound to p53 and induced its accumulation in tumor cells. RITA prevented p53-HDM-2 interaction in vitro and in vivo and affected p53 interaction with several negative regulators. RITA induced expression of p53 target genes and massive apoptosis in various tumor cells lines expressing wild-type p53. RITA suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effect in vivo. RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53.

Details

Language :
English
ISSN :
1078-8956
Volume :
10
Issue :
12
Database :
MEDLINE
Journal :
Nature medicine
Publication Type :
Academic Journal
Accession number :
15558054
Full Text :
https://doi.org/10.1038/nm1146