IST-MES1
Cat.No.: CSC-6273W
Species: Homo sapiens (Human)
Source: Pleural Effusion
Morphology: grown as monolayer, epithelial-like
Culture Properties: Adherent
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Viruses: PCR: HBV -, HCV -, HHV-8 -, HIV-1 -, HIV-2 -, HTLV-I/II -, MLV -, SMRV -
Identification of non-covalent inhibitors for the atypical peroxiredoxin PRDX5 as a therapeutic strategy in malignant pleural mesothelioma
Background
This bioRxiv preprint identifies peroxiredoxin 5 (PRDX5) as a subtype-specific vulnerability in malignant pleural mesothelioma (MPM). Using MOSAIC single-cell and spatial transcriptomics, PRDX5 is upregulated in epithelioid MPM and correlates with resistance to oxidative/nitrosative stress. Machine-learning-guided pocket detection and virtual screening of 3.6 million compounds followed by biochemical validation yielded 36 non-covalent PRDX5 inhibitors, including sub-micromolar hits. The study nominates PRDX5 as a therapeutic target and provides chemical starting points for redox-modulating precision oncology in MPM.
Key Findings
PRDX5 is significantly upregulated in epithelioid malignant pleural mesothelioma (MPM) compared with sarcomatoid and biphasic subtypes, validated in an independent cohort where 97% of tumors expressed PRDX5 in >50% of cells and 73% showed moderate-to-strong staining. MPM cell lines resist peroxynitrite and H2O2 more than healthy mesothelial cells, correlating with basal PRDX5 expression. PRDX5-positive malignant cells are enriched for hypoxia, ROS detoxification, and RNS metabolism signatures, particularly in tumor cores. Using AlloDeep/AlloTango, the authors identified three putative allosteric pockets (G85, alpha3, alpha5) and virtually screened 3.6 million compounds. Biochemical testing of 452 candidates yielded 36 non-covalent inhibitors (8% hit rate), including 13 potent and 23 weakly active hits. G85 and alpha3 leads showed IC50 values of 4.46 µM and 9.81 µM, respectively, with an azetidine-containing scaffold. This establishes PRDX5 as a subtype-specific MPM target and provides new chemical tools for redox-modulating cancer therapy.
Contribution
Creative Bioarray provided the human malignant pleural mesothelioma cell lines IST-MES-1 and IST-MES-2, which were used for PRDX5 target validation, oxidative/nitrosative stress sensitivity assays, and protein expression analysis. These cell models were essential for confirming PRDX5-mediated stress resistance and supporting the therapeutic rationale.
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