Identification of non-covalent inhibitors for the atypical peroxiredoxin PRDX5 as a therapeutic strategy in malignant pleural mesothelioma
Monserrat, J.; Montanari, F.; Laurent, V.; Ancey, P.-B.; Jean, N.; Jeannu, C.; Wang, G.; You, G.; Shen, Q.; Mac Kain, A.; Bareche, Y.; Herpin, L.; Jeremiah, N.; Codato, R.; Romagnoni, A.; Cornish, A. J.; Rozhavskaya, E.; Pattarini, L.; Petit, C.; Zindy, P.-J.; Shukla, J.; Gomez, S.; MOSAIC Consortium, ; Eckstein, M.; Youssef, A.; Keilholz, U.; Morkel, M.; Homicsko, K.; Saglietti, C.; Shi, L.; Zhang, J.; Pronier, E.
Show abstract
Malignant pleural mesothelioma (MPM) is an aggressive asbestos-linked cancer with limited therapeutic options and a dismal 5-year survival rate of [~]5%. While aberrant production of reactive oxygen and nitrogen species (ROS/RNS) is a hallmark of MPM, targeted approaches to exploit these redox vulnerabilities remain scarce. Here, using the MOSAIC multimodal cancer patient atlas, we identify Peroxiredoxin 5 (PRDX5) as being significantly upregulated in the epithelioid subtype of MPM. We show that MPM cells exhibit enhanced resistance to nitrosative and oxidative stress compared to healthy mesothelial cells, a phenotype correlated with basal PRDX5 expression. Next, utilising a machine learning guided discovery pipeline, we identified three putative allosteric pockets in PRDX5 and conducted a virtual screen of 3.6 million compounds. High-throughput biochemical validation of 452 candidates yielded 36 non-covalent hits, including sub-micromolar inhibitors. These findings establish PRDX5 as a novel, subtype specific therapeutic target in MPM and provide a chemical framework for the development of next-generation redox-modulating oncology treatments.
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