Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/103826
Title: A selective p53 activator and anticancer agent to improve colorectal cancer therapy
Authors: Ramos, Helena
Soares, Maria I. L. 
Silva, Joana
Raimundo, Liliana
Calheiros, Juliana
Gomes, Célia 
Reis, Flávio 
Monteiro, Filipe A.
Nunes, Cláudia
Reis, Salette 
Bosco, Bartolomeo
Piazza, Silvano
Domingues, Lucília
Chlapek, Petr
Vlcek, Petr
Fabian, Pavel
Rajado, Ana Teresa
Carvalho, A. T. P. 
Veselska, Renata
Inga, Alberto
Melo, Teresa M. V. D. Pinho e 
Saraiva, Lucília
Keywords: anticancer drug; colorectal cancer; p53 activator; targeted therapy
Issue Date: 13-Apr-2021
Publisher: Elsevier
Project: UIDB/50006/2020 
UID/BIO/04469/2019 
UIDB/04539/2020 
UIDP/04539/2020 
BioTecNorte operation (NORTE-01-0145-FEDER- 000004) 
Porto Neurosciences and Neurologic Disease Research Initiative at I3S (Norte-01-0145-FEDER-000008) 
Masaryk University (Project MUNI/A/1127/2019) 
Ministry of Education, Youth and Sports of the Czech Republic (project nos. LQ1605 and LM2018125) 
SFRH/BD/119144/2016 
SFRH/BD/117949/2016 
Fondazione AIRC (IG#18985, A.I.) 
Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences, PD/ 00016/2012). 
UIDB/00313/2020 
UIDP/00313/2020 
Serial title, monograph or event: Cell Reports
Volume: 35
Issue: 2
Abstract: Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.
URI: https://hdl.handle.net/10316/103826
ISSN: 22111247
DOI: 10.1016/j.celrep.2021.108982
Rights: openAccess
Appears in Collections:I&D CQC - Artigos em Revistas Internacionais
I&D ICBR - Artigos em Revistas Internacionais
I&D CIBB - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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