A selective p53 activator and anticancer agent to improve colorectal cancer therapy
Helena Ramos1, Maria I L Soares2, Joana Silva3
1LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
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.
Insights
A new drug, MANIO, reactivates the p53 pathway in cancer cells. This p53-activating drug shows efficacy against colorectal cancer with distinct p53 statuses, offering a promising targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The p53 pathway is frequently impaired in cancer, making its restoration a key therapeutic goal.
- Targeting the p53 pathway offers a promising strategy for developing novel anticancer treatments.
Purpose of the Study:
- To introduce MANIO, a novel small molecule designed to activate the p53 pathway.
- To evaluate MANIO's efficacy and mechanism of action in human cancer cells and preclinical models.
Main Methods:
- Assessed MANIO's effect on wild-type (WT) and mutant (mut) p53 activity in human cancer cells.
- Investigated MANIO's direct binding to the p53 DNA-binding domain and its impact on protein stability and function.
- Evaluated MANIO's anticancer efficacy in patient-derived colorectal cancer cells and xenograft mouse models.
- Assessed MANIO's synergy with conventional chemotherapy and its pharmacokinetic properties.
Main Results:
- MANIO selectively activates WTp53 and restores WT-like function to mutp53.
- MANIO enhances p53 thermal stability, DNA-binding, and transcriptional activity.
- MANIO demonstrated significant efficacy against colorectal cancer (CRC) in vitro and in vivo, irrespective of p53 status, with no observed side effects.
- MANIO exhibits favorable drug-likeness and pharmacokinetic properties, synergizing with chemotherapy.
Conclusions:
- MANIO is a potent p53-activating anticancer drug with broad applicability in cancers harboring WT or mutp53.
- MANIO shows promise as a clinical candidate for targeted anticancer therapy, especially for colorectal cancer patients.
- MANIO represents a significant advancement in p53-targeted cancer therapy.
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