TY  - JOUR
A1  - Baud, Matthias G. J.
A1  - Bauer, Matthias R.
A1  - Verduci, Lorena
A1  - Dingler, Felix A.
A1  - Patel, Ketan J.
A1  - Roy, Deeptee Horil
A1  - Jörger, Andreas C.
A1  - Fersht, Alan
T1  - Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines
T2  - European journal of medicinal chemistry
N2  - 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.
KW  - Mutant p53
KW  - Structure-based drug discovery
KW  - Anticancer therapy
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46862
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-468623
SN  - 1768-3254
SN  - 0223-5234
N1  - © 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/).
VL  - 152
SP  - 101
EP  - 114
PB  - Elsevier Science
CY  - Amsterdam [u .a.]
ER  -