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A selective p53 activator and anticancer agent to improve colorectal cancer therapy
H. Ramos, MIL. Soares, J. Silva, L. Raimundo, J. Calheiros, C. Gomes, F. Reis, FA. Monteiro, C. Nunes, S. Reis, B. Bosco, S. Piazza, L. Domingues, P. Chlapek, P. Vlcek, P. Fabian, AT. Rajado, ATP. Carvalho, R. Veselska, A. Inga, TMVD. Pinho E...
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Cell Press Free Archives
from 2012
Directory of Open Access Journals
from 2012
Free Medical Journals
from 2012
Freely Accessible Science Journals
from 2012-01-26
Open Access Digital Library
from 2012-01-01
Open Access Digital Library
from 2012-01-26
- MeSH
- Apoptosis drug effects genetics MeSH
- Cisplatin pharmacology MeSH
- Doxorubicin pharmacology MeSH
- Fluorouracil pharmacology MeSH
- HCT116 Cells MeSH
- Colorectal Neoplasms drug therapy genetics metabolism pathology MeSH
- Cell Cycle Checkpoints drug effects genetics MeSH
- Humans MeSH
- Mice, Nude MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Protein p53 agonists genetics metabolism MeSH
- Drug Discovery MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology MeSH
- Pyrroles chemical synthesis pharmacology MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Drug Synergism MeSH
- Thiazoles chemical synthesis pharmacology MeSH
- Protein Binding MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
1st Department of Surgery St Anne's University Hospital Brno Czech Republic
CEB Centre of Biological Engineering University of Minho Campus de Gualtar 4710 057 Braga Portugal
Clinical Academic Center of Coimbra Coimbra Portugal
CNC Center for Neuroscience and Cell Biology University of Coimbra 3004 504 Coimbra Portugal
i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto 4150 180 Porto Portugal
International Clinical Research Center St Anne's University Hospital Brno Czech Republic
Pain Research Group IBMC Instituto de Biologia Celular e Molecular 4150 180 Porto Portugal
University of Coimbra Center for Innovative Biomedicine and Biotechnology Coimbra Portugal
University of Coimbra Coimbra Chemistry Centre and Department of Chemistry 3004 535 Coimbra Portugal
References provided by Crossref.org
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