Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1.

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 3.1μM. Several of the most potent inhibitors were tested in a cellular assay that measures extent of vesicle recycling. Inhibiting EHD1 could potentially slow cancer invasivene

SUBMITTER: Kamens AJ 

PROVIDER: S-EPMC5844793 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature