A selective p53 activator and anticancer agent to improve colorectal cancer therapy
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/107439 https://doi.org/10.1016/j.celrep.2021.108982 |
Resumo: | 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. |
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A selective p53 activator and anticancer agent to improve colorectal cancer therapyanticancer drugcolorectal cancerp53 activatortargeted therapyAnimalsAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsApoptosisCell Cycle CheckpointsCell Line, TumorCell ProliferationCisplatinColorectal NeoplasmsDoxorubicinDrug DiscoveryDrug SynergismFemaleFluorouracilGene Expression Regulation, NeoplasticHCT116 CellsHumansMiceMice, NudeProtein BindingPyrrolesThiazolesTumor Suppressor Protein p53Xenograft Model Antitumor AssaysImpairment 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.Cell Press2021-04-13info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/107439http://hdl.handle.net/10316/107439https://doi.org/10.1016/j.celrep.2021.108982eng22111247Ramos, HelenaSoares, Maria I. L.Silva, JoanaRaimundo, LilianaCalheiros, JulianaGomes, CéliaReis, FlávioMonteiro, Filipe ANunes, CláudiaReis, SaletteBosco, BartolomeoPiazza, SilvanoDomingues, LucíliaChlapek, PetrVlcek, PetrFabian, PavelRajado, Ana TeresaCarvalho, A. T. P.Veselska, RenataInga, AlbertoPinho e Melo, Teresa M. V. D.Saraiva, Lucíliainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-17T08:43:36Zoai:estudogeral.uc.pt:10316/107439Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:23:47.797325Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
title |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
spellingShingle |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy Ramos, Helena anticancer drug colorectal cancer p53 activator targeted therapy Animals Antineoplastic Agents Antineoplastic Combined Chemotherapy Protocols Apoptosis Cell Cycle Checkpoints Cell Line, Tumor Cell Proliferation Cisplatin Colorectal Neoplasms Doxorubicin Drug Discovery Drug Synergism Female Fluorouracil Gene Expression Regulation, Neoplastic HCT116 Cells Humans Mice Mice, Nude Protein Binding Pyrroles Thiazoles Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays |
title_short |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
title_full |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
title_fullStr |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
title_full_unstemmed |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
title_sort |
A selective p53 activator and anticancer agent to improve colorectal cancer therapy |
author |
Ramos, Helena |
author_facet |
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 Pinho e Melo, Teresa M. V. D. Saraiva, Lucília |
author_role |
author |
author2 |
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 Pinho e Melo, Teresa M. V. D. Saraiva, Lucília |
author2_role |
author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
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 Pinho e Melo, Teresa M. V. D. Saraiva, Lucília |
dc.subject.por.fl_str_mv |
anticancer drug colorectal cancer p53 activator targeted therapy Animals Antineoplastic Agents Antineoplastic Combined Chemotherapy Protocols Apoptosis Cell Cycle Checkpoints Cell Line, Tumor Cell Proliferation Cisplatin Colorectal Neoplasms Doxorubicin Drug Discovery Drug Synergism Female Fluorouracil Gene Expression Regulation, Neoplastic HCT116 Cells Humans Mice Mice, Nude Protein Binding Pyrroles Thiazoles Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays |
topic |
anticancer drug colorectal cancer p53 activator targeted therapy Animals Antineoplastic Agents Antineoplastic Combined Chemotherapy Protocols Apoptosis Cell Cycle Checkpoints Cell Line, Tumor Cell Proliferation Cisplatin Colorectal Neoplasms Doxorubicin Drug Discovery Drug Synergism Female Fluorouracil Gene Expression Regulation, Neoplastic HCT116 Cells Humans Mice Mice, Nude Protein Binding Pyrroles Thiazoles Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays |
description |
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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-04-13 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/107439 http://hdl.handle.net/10316/107439 https://doi.org/10.1016/j.celrep.2021.108982 |
url |
http://hdl.handle.net/10316/107439 https://doi.org/10.1016/j.celrep.2021.108982 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
22111247 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Cell Press |
publisher.none.fl_str_mv |
Cell Press |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799134124415385600 |