Discovery of gamma-secretase inhibitors for breast cancer therapy through chemogenomic methods

Abstract

Breast cancer recurrence is often treated with hormonal and targeted chemotherapy. To this end, nicastrin, a protein involved in Notch signaling, has been associated with breast cancer recurrence. In this work, binding sites in nicastrin were identified. Binding interactions, and modes, of known nicastrin inhibitors were investigated using structure-based techniques. A binding site, termed the DYIGS binding site, (named after the conserved hydrophilic residues Asp336, Tyr337, Iso338, Gly339, and Ser340 found in the site) was identified. The binding mechanisms, and interactions, of known nicastrin inhibitors were investigated in the identified binding sites. This was done using binding free energy calculations, and per residue decomposition analysis. Residues such as Val138, Gln139. Asp143, Arg105 and Glu174 were discovered to be important in the interactions. The physicochemical properties and scaffold space of nicastrin inhibitors were investigated. Scaffold analysis and machine learning models identified specific connectivity containing a sulfon, sulfonamide, or sulfonamide connected to cyclic structures; and a halide or a halide connected to a benzene ring as being associated with high activity for nicastrin inhibition. Seven nicastrin inhibitors were discovered using this information. A preliminary antitumour bioassay confirmed the activity of six of the seven compounds, which inhibited tumour growth by more than 20%. However, three of these compounds demonstrated acceptable physicochemical and pharmacokinetic properties. The identification of these nicastrin actives opens new avenues for the development of breast cancer treatments.