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Identification of Phenazine‐Based MEMO1 Small‐Molecule Inhibitors: Virtual Screening, Fluorescence Polarization Validation, and Inhibition of Breast Cancer Migration
Author(s) -
Labrecque Courtney L.,
Hilton Cassidy N.,
Airas Justin,
Blake Alexis,
Rubenstein Kristen J.,
Parish Carol A.,
Pollock Julie A.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000797
Subject(s) - small molecule , virtual screening , fluorescence anisotropy , phenazine , chemistry , protein–protein interaction , motility , phosphorylation , computational biology , microbiology and biotechnology , biology , biochemistry , drug discovery , membrane
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 μ m . In addition, the most promising phenazine core compounds slow the migration of breast cancer cell lines in a scratch assay.