Identification of Phenazine-Based MEMO1 Small-Molecule Inhibitors: Virtual Screening, Fluorescence Polarization Validation, and Inhibition of Breast Cancer Migration.
Courtney L LabrecqueCassidy N HiltonJustin AirasAlexis BlakeKristen J RubensteinCarol A ParishJulie A PollockPublished in: ChemMedChem (2021)
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.
Keyphrases
- small molecule
- binding protein
- protein protein
- molecular dynamics simulations
- high throughput
- single molecule
- signaling pathway
- molecular docking
- cell therapy
- epithelial mesenchymal transition
- escherichia coli
- young adults
- atomic force microscopy
- risk assessment
- biofilm formation
- pseudomonas aeruginosa
- bone marrow
- cell proliferation
- mass spectrometry
- cystic fibrosis
- bioinformatics analysis
- locally advanced