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.
- MeSH
- Apoptosis drug effects genetics MeSH
- Cisplatin pharmacology MeSH
- Doxorubicin pharmacology MeSH
- Fluorouracil pharmacology MeSH
- HCT116 Cells MeSH
- Colorectal Neoplasms drug therapy genetics metabolism pathology MeSH
- Cell Cycle Checkpoints drug effects genetics MeSH
- Humans MeSH
- Mice, Nude MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Tumor Suppressor Protein p53 agonists genetics metabolism MeSH
- Drug Discovery MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology MeSH
- Pyrroles chemical synthesis pharmacology MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Drug Synergism MeSH
- Thiazoles chemical synthesis pharmacology MeSH
- Protein Binding MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
