Targeting the FN3K–Nrf2 axis: Discovery and pre-clinical evaluation of novel inhibitors for breast cancer therapy
Abstract
Introduction: Fructosamine-3-kinase (FN3K), a deglycation enzyme implicated in redox regulation through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, has emerged as a novel therapeutic target in breast cancer. Elevated FN3K activity enhances antioxidant defenses, promoting cancer cell survival and resistance to therapies. Pharmacological inhibition of FN3K may sensitize tumors to oxidative stress. Objective: This study aimed to identify and validate potent FN3K inhibitors through structure-based virtual screening (SBVS) and in vitro evaluation in breast cancer models. Methods: A homology-modeled FN3K structure was generated and validated using SWISS-MODEL, PROCHECK, and QMEAN. Compound libraries, including the Food and Drug Administration (FDA)-approved kinase inhibitors, World Health Organization (WHO) essential medicines, and anti-breast cancer agents, were screened using Schrödinger’s Glide module. Top-ranked compounds were prioritized based on binding affinity, molecular interactions, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. In vitro validation in MCF-7, BT-474, T-47D, and Vero cell lines included MTT cytotoxicity assay and evaluation of FN3K and Nrf2 expression through quantitative PCR (qPCR) and Western blotting. Statistical analyses were performed to assess the significance of observed effects. Results: Oxaliplatin, lansoprazole, and capivasertib exhibited strong binding affinities (Glide scores: −9.2 to −8.1…
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