Page 205 - EJMO-9-3

Eurasian Journal of Medicine

and Oncology

ORIGINAL RESEARCH ARTICLE
Targeting the FN3K–Nrf2 axis: Discovery and

pre-clinical evaluation of novel inhibitors for
breast cancer therapy

Erica Alves , Gurupadayya Bannimath* , and Prabitha Prabhakaran

Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher
Education & Research, Mysore, Karnataka, India

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
*Corresponding author: Drug Administration (FDA)-approved kinase inhibitors, World Health Organization
Gurupadayya Bannimath (WHO) essential medicines, and anti-breast cancer agents, were screened using
(bmgurupadayya@jssuni.edu.in) Schrödinger’s Glide module. Top-ranked compounds were prioritized based on
Citation: Alves E, binding affinity, molecular interactions, absorption, distribution, metabolism,
Bannimath G, Prabhakaran P. excretion, and toxicity (ADMET) profiling. In vitro validation in MCF-7, BT-474, T-47D,
Targeting the FN3K–Nrf2 axis:
Discovery and pre-clinical evaluation and Vero cell lines included MTT cytotoxicity assay and evaluation of FN3K and Nrf2
of novel inhibitors for breast cancer expression through quantitative PCR (qPCR) and Western blotting. Statistical analyses
therapy. Eurasian J Med Oncol. were performed to assess the significance of observed effects.
2025;9(3):197-225.
doi: 10.36922/EJMO025150114 Results: Oxaliplatin, lansoprazole, and capivasertib exhibited strong binding
affinities (Glide scores: −9.2 to −8.1 kcal/mol) and selective cytotoxicity in breast
Received: April 13, 2025
cancer cell lines (IC 90 – 110 µg/mL). qPCR analysis revealed >99% downregulation
50:
Revised: May 17, 2025 of FN3K, accompanied by significant suppression of Nrf2 in cancer cells. Minimal
Accepted: June 4, 2025 modulation was observed in Vero cells, indicating tumor selectivity. Western blotting
further corroborated the downregulation of FN3K and Nrf2 at the protein level.
Published online: July 28, 2025
Molecular dynamics (MD) simulations validated the binding stability of the lead
Copyright: © 2025 Author(s). small molecules, reinforcing their potential as effective inhibitors.
This is an Open-Access article
distributed under the terms of the Conclusion: The integrated in silico and in vitro analysis supports FN3K as a viable
Creative Commons Attribution therapeutic target in breast cancer. Oxaliplatin, lansoprazole, and capivasertib
License, permitting distribution, demonstrated strong FN3K inhibition and modulation of tumor redox homeostasis,
and reproduction in any medium,
provided the original work is suggesting their potential for further pre-clinical development as novel anti-cancer
properly cited. agents targeting metabolic adaptability.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Breast neoplasms; Fructosamine-3-kinase; Nuclear factor erythroid 2-related
regard to jurisdictional claims in
published maps and institutional factor 2 protein; Oxidative stress; Antineoplastic agents
affiliations.

Volume 9 Issue 3 (2025) 197 doi: 10.36922/EJMO025150114