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

Abstract

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 KI of 2.7 μm. In addition, the most promising phenazine core compounds slow the migration of breast cancer cell lines in a scratch assay.

Synthesis and biological activity of imidazole phenazine derivatives as potential inhibitors for NS2B-NS3 dengue protease

“…Imidazole phenazine derivatives was previously discovered as anticancer [ 28 ], antiproliferative [ 29 ], tuberculostatic [ 30 ] and chemsensor [ 31 ]. Amer et al were the first to report this ligand in 1999 [ 32 ], which was later characterized spectroscopically by Lei and co-workers in 2011 with substituents varied on the terminal benzene ring [ 33 ].…”