Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/103826
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Ramos, Helena | - |
dc.contributor.author | Soares, Maria I. L. | - |
dc.contributor.author | Silva, Joana | - |
dc.contributor.author | Raimundo, Liliana | - |
dc.contributor.author | Calheiros, Juliana | - |
dc.contributor.author | Gomes, Célia | - |
dc.contributor.author | Reis, Flávio | - |
dc.contributor.author | Monteiro, Filipe A. | - |
dc.contributor.author | Nunes, Cláudia | - |
dc.contributor.author | Reis, Salette | - |
dc.contributor.author | Bosco, Bartolomeo | - |
dc.contributor.author | Piazza, Silvano | - |
dc.contributor.author | Domingues, Lucília | - |
dc.contributor.author | Chlapek, Petr | - |
dc.contributor.author | Vlcek, Petr | - |
dc.contributor.author | Fabian, Pavel | - |
dc.contributor.author | Rajado, Ana Teresa | - |
dc.contributor.author | Carvalho, A. T. P. | - |
dc.contributor.author | Veselska, Renata | - |
dc.contributor.author | Inga, Alberto | - |
dc.contributor.author | Melo, Teresa M. V. D. Pinho e | - |
dc.contributor.author | Saraiva, Lucília | - |
dc.date.accessioned | 2022-11-30T10:52:08Z | - |
dc.date.available | 2022-11-30T10:52:08Z | - |
dc.date.issued | 2021-04-13 | - |
dc.identifier.issn | 22111247 | pt |
dc.identifier.uri | https://hdl.handle.net/10316/103826 | - |
dc.description.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. | pt |
dc.language.iso | eng | pt |
dc.publisher | Elsevier | pt |
dc.relation | UIDB/50006/2020 | pt |
dc.relation | UID/BIO/04469/2019 | pt |
dc.relation | UIDB/04539/2020 | pt |
dc.relation | UIDP/04539/2020 | pt |
dc.relation | BioTecNorte operation (NORTE-01-0145-FEDER- 000004) | pt |
dc.relation | Porto Neurosciences and Neurologic Disease Research Initiative at I3S (Norte-01-0145-FEDER-000008) | pt |
dc.relation | Masaryk University (Project MUNI/A/1127/2019) | pt |
dc.relation | Ministry of Education, Youth and Sports of the Czech Republic (project nos. LQ1605 and LM2018125) | pt |
dc.relation | SFRH/BD/119144/2016 | pt |
dc.relation | SFRH/BD/117949/2016 | pt |
dc.relation | Fondazione AIRC (IG#18985, A.I.) | pt |
dc.relation | Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences, PD/ 00016/2012). | pt |
dc.relation | UIDB/00313/2020 | pt |
dc.relation | UIDP/00313/2020 | pt |
dc.rights | openAccess | pt |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt |
dc.subject | anticancer drug; colorectal cancer; p53 activator; targeted therapy | pt |
dc.subject.mesh | Animals | pt |
dc.subject.mesh | Antineoplastic Agents | pt |
dc.subject.mesh | Antineoplastic Combined Chemotherapy Protocols | pt |
dc.subject.mesh | Apoptosis | pt |
dc.subject.mesh | Cell Cycle Checkpoints | pt |
dc.subject.mesh | Cell Line, Tumor | pt |
dc.subject.mesh | Cell Proliferation | pt |
dc.subject.mesh | Cisplatin | pt |
dc.subject.mesh | Colorectal Neoplasms | pt |
dc.subject.mesh | Doxorubicin | pt |
dc.subject.mesh | Drug Discovery | pt |
dc.subject.mesh | Drug Synergism | pt |
dc.subject.mesh | Female | pt |
dc.subject.mesh | Fluorouracil | pt |
dc.subject.mesh | Gene Expression Regulation, Neoplastic | pt |
dc.subject.mesh | HCT116 Cells | pt |
dc.subject.mesh | Humans | pt |
dc.subject.mesh | Mice | pt |
dc.subject.mesh | Mice, Nude | pt |
dc.subject.mesh | Protein Binding | pt |
dc.subject.mesh | Pyrroles | pt |
dc.subject.mesh | Thiazoles | pt |
dc.subject.mesh | Tumor Suppressor Protein p53 | pt |
dc.subject.mesh | Xenograft Model Antitumor Assays | pt |
dc.title | A selective p53 activator and anticancer agent to improve colorectal cancer therapy | pt |
dc.type | article | - |
degois.publication.firstPage | 108982 | pt |
degois.publication.issue | 2 | pt |
degois.publication.title | Cell Reports | pt |
dc.peerreviewed | yes | pt |
dc.identifier.doi | 10.1016/j.celrep.2021.108982 | pt |
degois.publication.volume | 35 | pt |
dc.date.embargo | 2021-04-13 | * |
uc.date.periodoEmbargo | 0 | pt |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.grantfulltext | open | - |
item.openairetype | article | - |
item.languageiso639-1 | en | - |
item.fulltext | Com Texto completo | - |
item.cerifentitytype | Publications | - |
crisitem.project.grantno | Associated Laboratory for Green Chemistry - Clean Technologies and Processes- REQUIMTE | - |
crisitem.project.grantno | Center for Innovative Biomedicine and Biotechnology - CIBB | - |
crisitem.project.grantno | Center for Innovative Biomedicine and Biotechnology | - |
crisitem.project.grantno | Coimbra Chemistry Center | - |
crisitem.project.grantno | Coimbra Chemistry Center | - |
crisitem.author.researchunit | CQC - Coimbra Chemistry Centre | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.researchunit | CQC - Coimbra Chemistry Centre | - |
crisitem.author.parentresearchunit | Faculty of Sciences and Technology | - |
crisitem.author.parentresearchunit | Faculty of Sciences and Technology | - |
crisitem.author.orcid | 0000-0001-8860-0470 | - |
crisitem.author.orcid | 0000-0002-7497-4129 | - |
crisitem.author.orcid | 0000-0003-3401-9554 | - |
crisitem.author.orcid | 0000-0003-2827-5527 | - |
crisitem.author.orcid | 0000-0003-3256-4954 | - |
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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1-s2.0-S2211124721002965-main.pdf | 5.01 MB | Adobe PDF | View/Open |
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