Small molecule induced reactivation of mutant p53 in cancer cells

Liu, Xiangrui, Wilcken, Rainer, Joerger, Andreas C, Chuckowree, Irina S, Amin, Jahangir, Spencer, John and Fersht, Alan R (2013) Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Research, 41 (12). pp. 6034-6044. ISSN 0305-1048

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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 μM 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 30 Apr 2013 09:38
Last Modified: 02 Jul 2019 20:21

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