Use of PROTACS as molecular probes of angiogenesis

E2-penta is an estradiol-peptide chemical chimera (ER-PROTAC) that binds to the estrogen receptor and targets it for proteolysis via the ubiquitin-mediated proteasome pathway. We show that E2-penta is a novel chemical genetic probe of angiogenesis as it blocks differentiation of vascular endothelial cells and potently inhibits angiogenic sprouting in vivo. Small molecules designed to specifically activate or inactivate protein functions have been useful to study biological processes. PROTACS are small molecule chimera which comprise a ligand and a peptide recognition motif for an E3 ligase. These novel reagents exploit the ubiquitin-mediated proteasome degradation pathway to target the ligand-bound protein for intracellular degradation. Here, we report that an estrogen receptor (ER)-targeting PROTACS that causes degradation of ER is able to potently inhibit endothelial cell differentiation in a three-dimensional angiogenic sprouting assay. These findings support the use of ER-targeting PROTACS as probes of angiogenesis.