The University of Southampton
University of Southampton Institutional Repository

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
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
0223-5234
101-114
Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e
Bauer, Matthias R.
606d5d28-6086-4988-89b5-fa07d3619022
Verduci, Lorena
9491d103-8e5c-4b42-a30f-8c29b9f51e9d
Dingler, Felix A.
3684da2d-7ff2-4c43-a795-b71ae34ac610
Patel, Ketan J.
b2b42f1a-599d-4747-9246-69379bf6648f
Horil Roy, Deeptee
0b339e75-96c7-4808-8ac9-4c07227723e8
Joerger, Andreas C.
69e42747-d541-4f47-92e5-d8ddd7d73c27
Fersht, Alan R.
b5145a83-e9cb-426f-8722-f60eb9aa59a5
Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e
Bauer, Matthias R.
606d5d28-6086-4988-89b5-fa07d3619022
Verduci, Lorena
9491d103-8e5c-4b42-a30f-8c29b9f51e9d
Dingler, Felix A.
3684da2d-7ff2-4c43-a795-b71ae34ac610
Patel, Ketan J.
b2b42f1a-599d-4747-9246-69379bf6648f
Horil Roy, Deeptee
0b339e75-96c7-4808-8ac9-4c07227723e8
Joerger, Andreas C.
69e42747-d541-4f47-92e5-d8ddd7d73c27
Fersht, Alan R.
b5145a83-e9cb-426f-8722-f60eb9aa59a5

Baud, Matthias G.J., Bauer, Matthias R., Verduci, Lorena, Dingler, Felix A., Patel, Ketan J., Horil Roy, Deeptee, Joerger, Andreas C. and Fersht, Alan R. (2018) Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines. European Journal of Medicinal Chemistry, 152, 101-114. (doi:10.1016/j.ejmech.2018.04.035).

Record type: Article

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

Text
1-s2.0-S0223523418303696-main - Version of Record
Available under License Creative Commons Attribution.
Download (3MB)

More information

Accepted/In Press date: 17 April 2018
e-pub ahead of print date: 21 April 2018
Published date: 25 May 2018

Identifiers

Local EPrints ID: 420323
URI: https://eprints.soton.ac.uk/id/eprint/420323
ISSN: 0223-5234
PURE UUID: a0217c5c-cb00-4fe4-875a-1a4879f5186a
ORCID for Matthias G.J. Baud: ORCID iD orcid.org/0000-0003-3714-4350

Catalogue record

Date deposited: 04 May 2018 16:30
Last modified: 14 Mar 2019 01:31

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×