期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 12, 页码 6034-6044出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt305
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资金
- ERC [P53LAZARUS]
- EPSRC-BBSRC-MRC Collaborative Network in Chemical Biology
- European Research Council Grant
- EPSRC [EP/I037229/1] Funding Source: UKRI
- MRC [MC_EX_G0901534] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/I037229/1] Funding Source: researchfish
- Medical Research Council [MC_EX_G0901534] Funding Source: researchfish
The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 mu M and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53.
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