Page 207 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology FN3K–Nrf2 axis inhibition in breast cancer

Pharmacological inhibition of FN3K represents a clonogenicity, and dose-sparing cytotoxic effects. FN3K
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novel therapeutic strategy to disrupt Nrf2-mediated is also implicated in mitochondrial regulation, glutathione
antioxidant defense mechanisms that enable cancer metabolism, and extracellular matrix (ECM) remodeling –
3
cell survival, proliferation, and resistance to therapy. hallmarks of tumor metabolic adaptation. These findings
Inhibiting FN3K may preserve Nrf2 in its glycated and position FN3K as a central modulator of cancer redox
transcriptionally inactive form, thereby increasing cancer biology and metabolism, offering therapeutic leverage
cell susceptibility to oxidative stress and potentially beyond Nrf2 regulation.
augmenting the therapeutic effectiveness of standard The present study investigates the therapeutic relevance
interventions, such as chemotherapy and radiotherapy. of FN3K inhibition in breast cancer, aiming to evaluate
However, despite its therapeutic promise, FN3K remains its potential to overcome drug resistance and enhance
an underexplored target in oncology, with limited progress treatment outcomes through an integrated in silico, in vitro,
in the identification and development of potent, selective and in vivo approach. This study utilizes three curated and
small molecule inhibitors. The pursuit of novel anti- pharmacologically validated compound databases as the
4
cancer agents has been significantly accelerated by the primary source for VS. The first database comprises the
emergence of SBVS, a pivotal component of computer- Food and Drug Administration (FDA)-approved kinase
aided drug discovery. SBVS enables the high-throughput inhibitors, which are designed to modulate aberrant kinase
computational screening of large chemical libraries against signaling – a hallmark of various malignancies. Given the
well-defined biological targets, leveraging structural central role of protein kinases in regulating key cellular
insights to identify potential lead compounds with processes and their frequent dysregulation in cancer, this
enhanced specificity and binding affinity. Compared to class of therapeutics represents one of the most extensively
traditional high-throughput screening methods, virtual targeted mechanisms in oncology. As of 2024, 80 small
screening (VS) offers substantial reductions in time, cost, molecule kinase inhibitors have received FDA approval, of
and resource expenditure, while improving hit rates through which 69 are indicated for cancer treatment, underscoring
rational design strategies. Moreover, recent advancements their clinical relevance in oncology. The second
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in docking algorithms, scoring functions, and ensemble- compound library was sourced from the World Health
based receptor modeling have further enhanced the Organization (WHO) Model List of Essential Medicines,
accuracy and success rate of SBVS in anti-cancer drug a globally endorsed collection of drugs selected based on
discovery. In addition to its role in Nrf2 regulation, recent their proven efficacy, safety, affordability, and significance
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advances have clarified that FN3K plays a multifaceted
role in cancer progression. FN3K deglycates key lysine and to public health. These compounds are clinically relevant,
arginine residues on Nrf2, enhancing its nuclear stability possess well-documented safety profiles, and are widely
applicable across diverse therapeutic settings. The third
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and enabling antioxidant response element (ARE)-driven dataset comprises FDA-approved therapeutics used
transcription of antioxidant and cytoprotective genes, in breast cancer management, including agents that
such as heme oxygenase-1 (HO-1), NAD(P)H quinone
dehydrogenase 1 (NQO1), and thioredoxin reductase act on various molecular targets, such as estrogen and
1 (TXNRD1), which collectively contribute to redox progesterone receptors, human epidermal growth factor
receptor 2 (HER2), and key regulators of the cell cycle.
homeostasis, chemoresistance, and tumor survival. 3,4,10 These drugs constitute the cornerstone of present treatment
Conversely, inhibiting FN3K impairs Nrf2’s interaction
with sMAF proteins, reduces nuclear translocation, and protocols and may present repurposing opportunities if
suppresses downstream antioxidant responses, thereby found to inhibit FN3K. Such dual-function compounds
sensitizing cancer cells to oxidative stress. Moreover, hold promise in attenuating both breast cancer progression
4,5
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and FN3K-driven metabolic adaptability.
FN3K modulates broader signaling networks through
glycation stress; the AGE and the receptor for AGE This study employed SBVS to identify potential small
(AGE-RAGE) systems stimulate oncogenic cascades, molecule binders with strong affinity toward the FN3K
including phosphoinositide 3-kinase/protein kinase B enzyme. SBVS involves molecular docking techniques
(PI3K/Akt), mitogen-activated protein kinase (MAPK), that simulate the interaction of candidate compounds
and Janus kinase/signal transducer and activator of within the enzyme’s active site, assessing their steric and
transcription 3 (JAK/STAT3), promoting epithelial– electrostatic compatibility. To predict binding affinities
mesenchymal transition, angiogenesis, and immune and rank potential candidates, a combination of scoring
evasion. Dual inhibition strategies (e.g., oxaliplatin + functions – spanning empirical methods, force field-
3,10
brusatol) have demonstrated enhanced reactive oxygen based approaches, and knowledge-driven models –
species (ROS)-mediated apoptosis, reduced migration and was utilized to evaluate the stability of ligand-enzyme

Volume 9 Issue 3 (2025) 199 doi: 10.36922/EJMO025150114