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Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220C stabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53-Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction in several p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediated transcriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy.

Original publication

DOI

10.1016/j.ejmech.2018.04.035

Type

Journal article

Journal

European journal of medicinal chemistry

Publication Date

05/2018

Volume

152

Pages

101 - 114

Addresses

Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom; Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, SO17 1BJ, UK. Electronic address: m.baud@soton.ac.uk.

Keywords

Tumor Cells, Cultured, Humans, Antineoplastic Agents, Drug Screening Assays, Antitumor, Signal Transduction, Cell Proliferation, Cell Survival, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Tumor Suppressor Protein p53, Benzothiazoles, Real-Time Polymerase Chain Reaction