Identification of Phenazine-Based MEMO1 Small-Molecule Inhibitors: Virtual Screening,Fluorescence Polarization Validation,and Inhibition of Breast Cancer Migration

Phosphorylation-dependent protein–protein interactions play a significant role in biological signaling pathways; therefore, small molecules that are capable of influencing these interactions can be valuable research tools and have potential as pharmaceutical agents. MEMO1 (mediator of ErbB2-cell driven motility) is a phosphotyrosine-binding protein that interacts with a variety of protein partners and has been found to be upregulated in breast cancer patients. Herein, we report the first small-molecule inhibitors of MEMO1 interactions identified through a virtual screening platform and validated in a competitive fluorescence polarization assay. Initial structure–activity relationships have been investigated for these phenazine-core inhibitors and the binding sites have been postulated using molecular dynamics simulations. The most potent biochemical inhibitor is capable of disrupting the large protein interface with a K_I of 2.7 μm . In addition, the most promising phenazine core compounds slow the migration of breast cancer cell lines in a scratch assay.