In Silico Repurposing of Nilotinib as a Type II Tyrosine Kinase Inhibitor to Overcome C797S-Mediated Resistance in EGFR-Mutant Non-small cell lung cancer
- 1HKUGA College
Abstract
Drug resistance due to mutations in the epidermal growth factor receptor (EGFR) remains a major, well-characterized bottleneck in the targeted therapy of non-small cell lung cancer (NSCLC). Among these mutations, C797S, emerging after treatment with third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib — prevents covalent drug binding to EGFR protein and results in current therapies ineffective. This study aims to identify and repurpose (Originally used to treat other conditions) potential FDA-approved TKIs capable of overcoming a particular C797S mutation through in silico molecular docking of 52 inhibitors (Type I–VI) against the EGFR T790M/C797S double mutant (PDB: 5ZWJ). AutoDock Vina was used to evaluate binding affinities to EGFR, with EAI045 serving as the reference fourth-generation inhibitor for validation because it shows promising allosteric inhibition but remains limited by its inability to prevent receptor dimerization. Results compared and confirmed the simulation of our docking model with a self-docking baseline of –10.46 kcal/mol for EAI045. Generally, screening revealed that Type II inhibitors exhibited the strongest binding affinity to the EGFR, with Nilotinib and Altiratinib (Note that Altiratinib is not an FDA-approved drug) outperforming EAI045. Nilotinib, an FDA-approved Type II Bcr-Abl inhibitor originally used in chronic myeloid leukemia (CML), displays hydrogen-bonding with the EGFR, sustaining the kinase in its inactive DFG-out conformation when it’s binding. This mechanism prevents ATP binding and stops auto phosphorylation, allowing inhibitory effects even in environments with high ATP concentration by inhibiting the EGFR protein orthosterically. Results show that Nilotinib is a promising candidate to be repurposed into a 4th generation (Post-Osimertinib) TKI for EGFR with C797S mutation NSCLCs. As repurposing drugs have a quicker and cheaper administrative+pre-clinical testing process compared to de novo drug discoveries, by aiming to repurpose drugs we can accelerate clinical translation. While further in vitro and in vivo validation is necessary, this study provides a foundation for developing targeted therapies against the C797S-mediated resistance in advanced NSCLC.
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BibTeX
@misc{tsang2026silico,
title = {{In Silico Repurposing of Nilotinib as a Type II Tyrosine Kinase Inhibitor to Overcome C797S-Mediated Resistance in EGFR-Mutant Non-small cell lung cancer}},
author = {Yik Long Matthew Tsang and Julian Ng},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008183/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008183/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - In Silico Repurposing of Nilotinib as a Type II Tyrosine Kinase Inhibitor to Overcome C797S-Mediated Resistance in EGFR-Mutant Non-small cell lung cancer
AU - Yik Long Matthew Tsang
AU - Julian Ng
PY - 2026
DA - 2026/09/01
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008183/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008183/v1
AB - Drug resistance due to mutations in the epidermal growth factor receptor (EGFR) remains a major, well-characterized bottleneck in the targeted therapy of non-small cell lung cancer (NSCLC). Among these mutations, C797S, emerging after treatment with third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib — prevents covalent drug binding to EGFR protein and results in current therapies ineffective. This study aims to identify and repurpose (Originally used to treat other conditions) potential FDA-approved TKIs capable of overcoming a particular C797S mutation through in silico molecular docking of 52 inhibitors (Type I–VI) against the EGFR T790M/C797S double mutant (PDB: 5ZWJ). AutoDock Vina was used to evaluate binding affinities to EGFR, with EAI045 serving as the reference fourth-generation inhibitor for validation because it shows promising allosteric inhibition but remains limited by its inability to prevent receptor dimerization. Results compared and confirmed the simulation of our docking model with a self-docking baseline of –10.46 kcal/mol for EAI045. Generally, screening revealed that Type II inhibitors exhibited the strongest binding affinity to the EGFR, with Nilotinib and Altiratinib (Note that Altiratinib is not an FDA-approved drug) outperforming EAI045. Nilotinib, an FDA-approved Type II Bcr-Abl inhibitor originally used in chronic myeloid leukemia (CML), displays hydrogen-bonding with the EGFR, sustaining the kinase in its inactive DFG-out conformation when it’s binding. This mechanism prevents ATP binding and stops auto phosphorylation, allowing inhibitory effects even in environments with high ATP concentration by inhibiting the EGFR protein orthosterically. Results show that Nilotinib is a promising candidate to be repurposed into a 4th generation (Post-Osimertinib) TKI for EGFR with C797S mutation NSCLCs. As repurposing drugs have a quicker and cheaper administrative+pre-clinical testing process compared to de novo drug discoveries, by aiming to repurpose drugs we can accelerate clinical translation. While further in vitro and in vivo validation is necessary, this study provides a foundation for developing targeted therapies against the C797S-mediated resistance in advanced NSCLC.
ER -