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Drug repositioning and experimental validation for targeting ZZ domain of p62 as a cancer treatment
Ali Kian Saei1, Narjes Asghari1, Babak Jahangiri1
1Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran.
Abstract:
Cancer treatment is often confounded by development of resistance to chemotherapy. This research explores the complex relationship between p62 (also known as SQSTM1), a multifunctional protein central in cancer signaling pathways - especially the NF-κB pathway - and chemoresistance. Our data indicate that disruption of the interaction between p62 and the serine/threonine protein kinase RIP1 is a viable strategy to counteract NF-κB activation and overcome chemoresistance. Employing a comprehensive drug repositioning approach, we utilized bioinformatics tools to perform docking, virtual screening, absorption, distribution, metabolism, and excretion analyses, toxicity analysis, and molecular dynamics simulations to identify FDA-approved drugs that prevent the binding of p62 to RIP1. Notable candidates, particularly montelukast and asunaprevir, blocked the p62-RIP1 interaction, establishing a basis for potential therapeutic interventions against chemoresistant cancers. This study highlights the critical role of the ZZ domain of p62 protein in chemotherapy resistance and sheds light on the possibility of repurposing existing drugs for novel applications in cancer treatment. Our findings provide a solid groundwork for preclinical studies.
Insights
Researchers found that blocking the interaction between p62 and RIP1 protein can overcome chemotherapy resistance in cancer. FDA-approved drugs like montelukast and asunaprevir show promise for treating chemoresistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Chemotherapy resistance is a major challenge in cancer treatment.
- The protein p62 (SQSTM1) plays a key role in cancer signaling pathways, including NF-κB.
- Understanding p62's role in chemoresistance is crucial for developing new therapies.
Purpose of the Study:
- To investigate the role of the p62-RIP1 interaction in chemoresistance.
- To identify FDA-approved drugs that can disrupt the p62-RIP1 interaction.
- To explore novel therapeutic strategies for chemoresistant cancers.
Main Methods:
- Utilized a drug repositioning approach with bioinformatics tools.
- Performed molecular docking, virtual screening, ADMET, toxicity analysis, and molecular dynamics simulations.
- Identified drugs targeting the p62-RIP1 interaction.
Main Results:
- Disrupting the p62-RIP1 interaction is a viable strategy to counteract NF-κB activation and overcome chemoresistance.
- Montelukast and asunaprevir were identified as potential candidates that block the p62-RIP1 interaction.
- The ZZ domain of p62 is critical in chemotherapy resistance.
Conclusions:
- Repurposing existing drugs like montelukast and asunaprevir offers a promising avenue for treating chemoresistant cancers.
- Targeting the p62-RIP1 interaction presents a novel therapeutic strategy.
- This study provides a foundation for preclinical investigations into novel cancer treatments.
