期刊
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 85
卷 85, 期 -, 页码 375-404出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-biochem-060815-014710
关键词
p53 family; protein evolution; signaling pathways; cancer therapy; drug design; small-molecule stabilizers
资金
- Medical Research Council [MC_UP_A024_1010, MC_EX_G0901534] Funding Source: Medline
- MRC [MC_EX_G0901534, MC_UP_A024_1010] Funding Source: UKRI
Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. We trace the structural evolution of the p53 pathway, from germ-line surveillance in simple multicellular organisms to its pluripotential role in humans.
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