Page 214 - EJMO-9-3

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

showed strong binding, interacting with CYS A:24, LYS
A:41, and ASP A:217, which are key active site residues.
This supports their potential as FN3K inhibitors. Ritonavir
(−8.7 kcal/mol) demonstrated a strong binding score
but interacted with fewer critical residues, indicating
potential, but possibly with reduced specificity for FN3K
inhibition. In contrast, amiloride (−6.9 kcal/mol) and
1-DMF (−6.1 kcal/mol) displayed weaker binding and
fewer significant interactions, suggesting they may not
be ideal candidates as FN3K inhibitor. The 3D and 2D
protein–ligand interaction profiles of all six hit molecules,
including their binding residues and docking scores, are
presented in Figure S2.
This study was intentionally structured as a focused
Figure 4. Three-dimensional structure of the final modeled human drug repurposing investigation aimed at identifying
FN3K protein. The 3D structure is depicted using a rainbow color clinically relevant FN3K inhibitors with high
gradient, ranging from the N-terminus (blue) to the C-terminus (red), translational potential. The screening FDA-approved
to illustrate the overall fold. The model features a compact globular kinase inhibitors, WHO-listed essential medicines, and
conformation with prominent α-helices and β-sheets. Following anti-breast cancer agents offers multiple advantages in
validation by stereochemical and sequence-based assessments, this
structure was chosen for subsequent molecular docking and functional oncology drug discovery, including established safety
analysis profiles, known pharmacokinetic properties, and
Abbreviations: FN3K: Fructosamine-3-kinase regulatory familiarity – factors that collectively expedite
the clinical translation process. This strategic approach
to ensure drug-likeness and a preliminary ADMET allowed us to rapidly transition from in silico screening
assessment to evaluate their pharmacokinetic profiles to in vitro validation across diverse breast cancer
and safety considerations. The detailed results of the subtypes.
ADMET screening, including physicochemical properties, Our findings with oxaliplatin, lansoprazole, and
drug-likeness, solubility, gastrointestinal absorption,
and cytochrome P450 (CYP) interactions, are provided capivasertib underscore the feasibility and effectiveness
of this repurposing-centric approach. These compounds
in Supplementary Tables S1-S5 and Figure S1. These demonstrated strong FN3K inhibition, selective
combined analyses enabled the exclusion of compounds cytotoxicity toward malignant cells, and downregulation
with suboptimal properties or toxicity risks. Ultimately, of redox-associated transcriptional programs, thereby
the final selection of hit molecules was based on a holistic validating their mechanistic relevance.
assessment encompassing VS performance, rank-based
scoring, favorable physicochemical characteristics, and Nonetheless, we acknowledge that restricting the
acceptable ADMET profiles. These molecules serve as chemical library to approved drugs inherently limits the
promising leads for subsequent validation through in vitro structural diversity and novelty of potential hits. Exploring
enzyme inhibition assays and advanced computational broader chemical space, including natural product
analyses, aimed at substantiating their potential as scaffolds, macrocyclic inhibitors, and de novo designed
therapeutic inhibitors of FN3K. Docking scores, expressed chemical entities, may uncover novel binding chemotypes
in kcal/mol, reflect the predicted binding affinity between and allosteric inhibitors with improved specificity and
ligand and target, with more negative values corresponding potency. Accordingly, future studies will integrate VS of
to stronger interactions. natural compound libraries (e.g., NPASS, ZINC Natural
Products), fragment-based approaches, and machine
3.1.4. Key findings from VS learning-assisted scaffold hopping to identify next-
Oxaliplatin (−9.2 kcal/mol) exhibited the highest binding generation FN3K inhibitors.
affinity, forming stable interactions with residues CYS Thus, while our repurposing approach lays a pragmatic
A:24, ILE A:25, LYS A:41, MET A:51, ASP A:217, and TRP foundation for translational success, it also opens avenues
A:219. These residues are likely critical for FN3K activity, for expanded pharmacophore discovery and rational
suggesting a strong inhibitory potential. Lansoprazole design of structurally novel inhibitors tailored to FN3K’s
(−8.6 kcal/mol) and capivasertib (−8.1 kcal/mol) also catalytic and regulatory domains.

Volume 9 Issue 3 (2025) 206 doi: 10.36922/EJMO025150114