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

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

  • Eur J Med Chem. 2018 May 25;152:101-114. doi: 10.1016/j.ejmech.2018.04.035.
Matthias G J Baud 1,  Matthias R Bauer 2,  Lorena Verduci 2,  Felix A Dingler 2,  Ketan J Patel 2,  Deeptee Horil Roy 2,  Andreas C Joerger 3,  Alan R Fersht 4
Affiliations

Affiliations

  • 1 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.
  • 2 Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom.
  • 3 Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom; German Cancer Consortium (DKTK), German Cancer Center (DKFZ), 69120 Heidelberg, Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main, 60438, Germany.
  • 4 Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, United Kingdom. Electronic address: arf25@cam.ac.uk.
PMID: 29702446 DOI: 10.1016/j.ejmech.2018.04.035
Abstract

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.

Keywords

Anticancer therapy; Mutant p53; Structure-based drug discovery.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120373
    98.76%, p53-Y220C稳定剂
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