Tackling the Moving Mutant Target: Taxifolin Derivatives as Novel Putative E571K Exportin-1 Inhibitors for KRAS-mutant Lung Adenocarcinoma

Introduction: The association between drug resistance and genomic mutations underscores their clinical importance in cancer treatment strategies. One such mutation is the E571K alteration in the exportin-1 gene (XPO1), which affects nuclear export signals. Exportin-1 deregulation contributes to oncogenic conditions, including KRAS-mutant lung adenocarcinoma, while this mutation is more common in haematological malignancies, it also occurs in solid tumors like lung adenocarcinoma. Developing selective inhibitors of nuclear export signals (SINEs), such as Selinexor, could improve the prognosis for this challenging condition. However, current SINEs have limitations in potency and safety when used alone or in combination therapy.Aim: To establish, through molecular modeling, safe and clinically acceptable putative antagonists of E571K-mutated exportin-1 among the bioactive compounds in various parts of Juglans mandshurica.Methods: The bioactive compounds were subjected to the compendium of drug-likeness and lead-likeness filter workflows before docking of the resultant compounds into E571K exportin-1 active site using PyRx AutoDock vina to establish their binding affinity and interaction profile. The evolutionary algorithm of Osiris DataWarrior software, as well as lead-likeness filter were employed for the generation of novel non-promiscuous analogs of the lead compound with better putative selectivity and clinical acceptability as E571K Exportin-1 antagonists.Results: The findings of this study present taxifolin as the putatively effective and lead-like E571K Exportin-1 inhibitor with high potential of qualifying for clinical evaluation but is associated with high promiscuity tendency in high throughput screening. The evolutionary derivation of novel analogs of the compound, however, results in the generation of putatively non-promiscuous, non-toxic, and lead-like E571K Exportin-1 antagonists with high synthetic accessibility and clinical developability for evaluation in the strategy for the treatment of drug-resistant KRAS-mutant lung adenocarcinoma condition.)