1. Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1
- Author
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Alissa J. Kamens, Joshua A. Kritzer, Robyn J. Eisert, Kaley M. Mientkiewicz, Charles R. Mace, and Jenna A. Walz
- Subjects
0301 basic medicine ,Receptor recycling ,Macrocyclic Compounds ,Alkylation ,Clinical Biochemistry ,Vesicular Transport Proteins ,Pharmaceutical Science ,Fluorescence Polarization ,Plasma protein binding ,Sulfides ,Peptides, Cyclic ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Thioether ,Drug Discovery ,Humans ,Receptor ,Molecular Biology ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,Vesicle ,Cellular Assay ,Organic Chemistry ,Signal transducing adaptor protein ,Cyclic peptide ,Kinetics ,030104 developmental biology ,chemistry ,Molecular Medicine ,HeLa Cells ,Protein Binding - Abstract
Recycling of receptors from the endosomal recycling compartment to the plasma membrane is a critical cellular process, and recycling is particularly important for maintaining invasiveness in solid tumors. In this work, we continue our efforts to inhibit EHD1, a critical adaptor protein involved in receptor recycling. We applied a diversity-oriented macrocyclization approach to produce cyclic peptides with varied conformations, but that each contain a motif that binds to the EH domain of EHD1. Screening these uncovered several new inhibitors for EHD1’s EH domain, the most potent of which bound with a K(d) of 3.1 μM. Several of the most potent inhibitors were tested in a cellular assay that measures extent of vesicle recycling. Inhibiting EHD1 could potentially slow cancer invasiveness and metastasis, and these cyclic peptides represent the most potent inhibitors of EHD1 to date.
- Published
- 2018
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