Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1

Publication date: Available online 18 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Alissa J. Kamens, Kaley M. Mientkiewicz, Robyn J. Eisert, Jenna A. Walz, Charles R. Mace, Joshua A. Kritzer
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 Kd 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.

Graphical abstract

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