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

CNC Center for Neuroscience and Cell Biology University of Coimbra 3004 504 Coimbra Portugal

Departamento de Biomedicina Unidade de Biologia Experimental FMUP Faculdade de Medicina da Universidade do Porto 4200 319 Porto Portugal; Pain Research Group IBMC Instituto de Biologia Celular e Molecular 4150 180 Porto Portugal; i3S Instituto de Investigação e Inovação em Saúde Universidade do Porto 4150 180 Porto Portugal

Department CIBIO Laboratory of Transcriptional Networks University of Trento via Sommarive 9 38123 Trento Italy

Department of Oncological and Experimental Pathology Masaryk Memorial Cancer Institute Brno Czech Republic

Laboratory of Tumor Biology Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic; International Clinical Research Center St Anne's University Hospital Brno Czech Republic

LAQV REQUIMTE Laboratório de Microbiologia Departamento de Ciências Biológicas Faculdade de Farmácia Universidade do Porto Porto Portugal

LAQV REQUIMTE Laboratório de Química Aplicada Departamento de Ciências Químicas Faculdade de Farmácia Universidade do Porto Porto Portugal

University of Coimbra Coimbra Chemistry Centre and Department of Chemistry 3004 535 Coimbra Portugal

University of Coimbra Coimbra Institute for Clinical and Biomedical Research Coimbra Portugal

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