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


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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

Year of publication 2021
Type Article in Periodical
Magazine / Source Cell Reports
MU Faculty or unit

Faculty of Science

Web https://doi.org/10.1016/j.celrep.2021.108982
Doi http://dx.doi.org/10.1016/j.celrep.2021.108982
Keywords p53 activator; anticancer drug; colorectal cancer; targeted therapy
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.
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