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@article{1820278,
author = {Ramos, Helena and Soares, Maria I.L and Silva, Joana and Raimundo, Liliana and Calheiros, Juliana and Gomes, Célia and Reis, Flávio and Monteiro, Filipe A. and Nunes, Cláudia and Reis, Salette and Bosco, Bartolomeo and Piazza, Silvano and Domingues, Lucília and Chlapek, Petr and Vlček, Petr and Fabian, Pavel and Rajado, Ana Teresa and Carvalho, A.T.P. and Veselská, Renata and Inga, Alberto and Melo, Teresa M.V.D. Pinho e and Saraiva, Lucília},
article_location = {Cambridge},
article_number = {2},
doi = {http://dx.doi.org/10.1016/j.celrep.2021.108982},
keywords = {p53 activator; anticancer drug; colorectal cancer; targeted therapy},
language = {eng},
issn = {2211-1247},
journal = {Cell Reports},
title = {A selective p53 activator and anticancer agent to improve colorectal cancer therapy},
url = {https://doi.org/10.1016/j.celrep.2021.108982},
volume = {35},
year = {2021}
}
TY - JOUR
ID - 1820278
AU - 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 - Vlček, Petr - Fabian, Pavel - Rajado, Ana Teresa - Carvalho, A.T.P. - Veselská, Renata - Inga, Alberto - Melo, Teresa M.V.D. Pinho e - Saraiva, Lucília
PY - 2021
TI - A selective p53 activator and anticancer agent to improve colorectal cancer therapy
JF - Cell Reports
VL - 35
IS - 2
SP - 108982
EP - 108982
PB - Cell Press
SN - 22111247
KW - p53 activator
KW - anticancer drug
KW - colorectal cancer
KW - targeted therapy
UR - https://doi.org/10.1016/j.celrep.2021.108982
N2 - 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.
ER -
RAMOS, Helena, Maria I.L SOARES, Joana SILVA, Liliana RAIMUNDO, Juliana CALHEIROS, Célia GOMES, Flávio REIS, Filipe A. MONTEIRO, Cláudia NUNES, Salette REIS, Bartolomeo BOSCO, Silvano PIAZZA, Lucília DOMINGUES, Petr CHLAPEK, Petr VLČEK, Pavel FABIAN, Ana Teresa RAJADO, A.T.P. CARVALHO, Renata VESELSKÁ, Alberto INGA, Teresa M.V.D. Pinho e MELO and Lucília SARAIVA. A selective p53 activator and anticancer agent to improve colorectal cancer therapy. \textit{Cell Reports}. Cambridge: Cell Press, 2021, vol.~35, No~2, p.~108982-109005. ISSN~2211-1247. Available from: https://dx.doi.org/10.1016/j.celrep.2021.108982.
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