RT Journal Article
T1 Drug repositioning and experimental validation for targeting ZZ domain of p62 as a cancer treatment
A1 Saei, Ali Kian
A1 Asghari, Narjes
A1 Jahangiri, Babak
A1 Cordani, Marco
A1 Nayeri, Zahra
A1 Fard, Najaf Allahyari
A1 Djavaheri-Mergny, Mojgan
A1 Moosavi, Mohammad Amin
AB 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.
PB Elsevier
SN 0010-4825
YR 2025
FD 2025-02-20
LK https://hdl.handle.net/20.500.14352/119186
UL https://hdl.handle.net/20.500.14352/119186
LA eng
NO Saei, A. K., Asghari, N., Jahangiri, B., Cordani, M., Nayeri, Z., Fard, N. A., Djavaheri-Mergny, M., & Moosavi, M. A. (2025). Drug repositioning and experimental validation for targeting ZZ domain of p62 as a cancer treatment. Computers in Biology and Medicine, 188. https://doi.org/10.1016/J.COMPBIOMED.2025.109757
NO This study was funded by the National Institute of Genetic Engineering and Biotechnology (NIGEB) (Grant no. 884), Tehran, Iran. M.C is supported by grant RYC2021-031003I funded by MICIU/AEI/10.13039/501100011033 and, by European Union NextGenerationEU/PRTR. M.D-M is supported by funds from the Institut National de la Santé et de la Recherche Médicale (Inserm) and grants from the Agence National de la Recherche (ANR-21-CE44-0016 (CISCO), ANR-23-CE13-0013 (JANUS), INCa (PLBIO23-216-2023-181).
NO National Institute of Genetic Engineering and Biotechnology (Irán)
NO Ministerio de Ciencia e Innovación (España)
NO European Commission
NO Universidad Complutense de Madrid
NO Institut national de la santé et de la recherche médicale (France)
NO Agence nationale de la recherche (France)
DS Docta Complutense
RD 14 dic 2025