Chemical space analysis of gamma-secretase inhibitors: A cheminformatic characterization

The gamma-secretase complex has been identified as an essential target for the treatment of breast cancer through its central role in regulating notch signaling. However, drugs targeting this complex have not made much headway in clinical trials. Understanding the chemical space of gamma-secretase inhibitors (GSIs) in relation to FDA approved drugs is useful for repurposing small molecules. In this study, the chemical space of gamma-secretase inhibitors, FDA approved and breast cancer drugs were characterized through analysis of the physicochemical property space through principal component analysis, t-SNE, scaffold diversity, activity cliffs and QSAR modeling. The GSIs occupied a compact beyond the Rule of Five subregion of the approved drug-like space, with higher aromaticity, greater lipophilicity and lower polarity than the broader approved drug set. Enriched GSI scaffolds include sulfonamide-biaryl systems, lactam-sulfonamides and nitrogen-rich heterocycles, which are almost absent in the FDA approved drug space. The QSAR model was trained on 2182 GSIs (AUC =0.97, R =0.93, Spearman rho =0.89) and retained a performance under scaffold held-out cross validation (AUC =0.89±0.02). It identified halogenated aromatics, sulfonamide-non-aromatic ring combinations and fused hetero-polycyclic systems as structural features predictive of high pIC 50 and identified five FDA approved drugs bearing these GSIassociated structural motifs as candidates for experimental validation of gamma-secretase inhibitory activity in the context of breast cancer treatment.