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.

A selective p53 activator and anticancer agent to improve colorectal cancer therapy / Ramos, H.; Soares, M. I. L.; Silva, J.; Raimundo, L.; Calheiros, J.; Gomes, C.; Reis, F.; Monteiro, F. A.; Nunes, C.; Reis, S.; Bosco, B.; Piazza, S.; Domingues, L.; Chlapek, P.; Vlcek, P.; Fabian, P.; Rajado, A. T.; Carvalho, A. T. P.; Veselska, R.; Inga, A.; Pinho e Melo, T. M. V. D.; Saraiva, L.. - In: CELL REPORTS. - ISSN 2211-1247. - 35:2(2021), pp. 10898201-108982e8. [10.1016/j.celrep.2021.108982]

A selective p53 activator and anticancer agent to improve colorectal cancer therapy

Bosco B.;Piazza S.;Inga A.;
2021-01-01

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.
2021
2
Ramos, H.; Soares, M. I. L.; Silva, J.; Raimundo, L.; Calheiros, J.; Gomes, C.; Reis, F.; Monteiro, F. A.; Nunes, C.; Reis, S.; Bosco, B.; Piazza, S.; Domingues, L.; Chlapek, P.; Vlcek, P.; Fabian, P.; Rajado, A. T.; Carvalho, A. T. P.; Veselska, R.; Inga, A.; Pinho e Melo, T. M. V. D.; Saraiva, L.
A selective p53 activator and anticancer agent to improve colorectal cancer therapy / Ramos, H.; Soares, M. I. L.; Silva, J.; Raimundo, L.; Calheiros, J.; Gomes, C.; Reis, F.; Monteiro, F. A.; Nunes, C.; Reis, S.; Bosco, B.; Piazza, S.; Domingues, L.; Chlapek, P.; Vlcek, P.; Fabian, P.; Rajado, A. T.; Carvalho, A. T. P.; Veselska, R.; Inga, A.; Pinho e Melo, T. M. V. D.; Saraiva, L.. - In: CELL REPORTS. - ISSN 2211-1247. - 35:2(2021), pp. 10898201-108982e8. [10.1016/j.celrep.2021.108982]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/333840
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