e20716 Background: Non-small cell lung cancer (NSCLC) in non-smoking women represents a biologically distinct subgroup in which actionable therapeutic targets can be identified and may also have broader relevance across diverse NSCLC subgroups. This study aimed to identify hub genes from tumor-normal transcriptomics and to identify druggable targets using drug–gene interaction mining, structure-based docking, and in silico developability profiling. Methods: Microarray data from the publicly accessible dataset GSE19804 (Affymetrix U133 Plus 2.0), comprising 60 tumors and 60 paired adjacent normal lung tissues, were analyzed utilizing GEO2R/limma. Differentially expressed genes were identified with a significance threshold of p ≤ 0.05 and |logFC| ≥ 1.0. Protein–protein interactions (PPI) were constructed using STRING with a combined score of ≥ 0.700 and a false discovery rate (FDR) of 1%, and these interactions were ranked by degree centrality in Cytoscape/cytoHubba. Results: PPI results revealed ten highly connected upregulated hubs: CDK1, CCNB1, CCNA2, KIF11, BUB1, TOP2A, DLGAP5, NUF2, MELK, and PBK, with a high-confidence and robust integration of KIF11 (degree 57; mean score 0.973). DGIdb analysis prioritized KIF11 as the most actionable hub, led by ispinesib–KIF11 and filanesib, followed by litronesib, AZD-4877, dimethylenastron, S-Trityl-L-cystein (STLC). Docking to the KIF11 L5 allosteric pocket (PDB 4A5Y) showed stable binding across inhibitors (–8.7 to –10.5 kcal/mol), with ispinesib and STLC strongest (–10.5), driven by Glu116-centered hydrogen bonding and extensive hydrophobic/aromatic contacts. OSIRIS and ADMET predictions indicated overall oral drug-like properties, high intestinal absorption, and no predicted AMES mutagenicity, while differentiating safety/liability profiles (Table). Notably, STLC and dimethylenastron exhibited more favorable predicted safety profiles, including lower hERG and hepatotoxicity probabilities, compared with ispinesib, which showed higher liability signals. Conclusions: This study highlights STLC as a promising KIF11 inhibitor with strong structural engagement and favorable in silico developability, alongside ispinesib as a validated reference, supporting KIF11 as a central, druggable vulnerability in female non-smoking NSCLC with potential relevance across broader NSCLC subgroups. In silico binding, ADMET, and OSIRIS drug-likeness profiles of KIF11 inhibitors. Drug Binding Affinity (kcal/mol) HIA AMES hERG Risk Overall Drug Score (OSIRIS) Ispinesib –10.5 High Negative High 0.36 S-Trityl-L-cysteine (STLC) –10.5 High Negative Low 0.38 Filanesib –9.0 High Negative Low 0.35 AZD-4877 –9.1 High Negative Moderate 0.56 Dimethylenastron –9.0 High Negative Very Low 0.56 Litronesib –8.7 High Negative Low 0.33 Abbreviations: HIA, human intestinal absorption; AMES, Ames mutagenicity test; hERG, human ether-a-go-go–related gene channel.
Yusuf Açıkgöz (Thu,) studied this question.