Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines

  • 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.
Metadaten
Author:Matthias G. J. Baud, Matthias R. Bauer, Lorena Verduci, Felix A. Dingler, Ketan J. Patel, Deeptee Horil Roy, Andreas C. Jörger, Alan Fersht
URN:urn:nbn:de:hebis:30:3-468623
DOI:https://doi.org/10.1016/j.ejmech.2018.04.035
ISSN:1768-3254
ISSN:0223-5234
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29702446
Parent Title (English):European journal of medicinal chemistry
Publisher:Elsevier Science
Place of publication:Amsterdam [u .a.]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/04/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/07/17
Tag:Anticancer therapy; Mutant p53; Structure-based drug discovery
Volume:152
Page Number:14
First Page:101
Last Page:114
Note:
© 2018 MRC Laboratory of Molecular Biology. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
HeBIS-PPN:435675664
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0