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Online ISSN: 1860-7187
June 15, 2010
VIP: Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor-Targeting PROTACs
Kedra Cyrus, Marie Wehenkel, Eun-Young Choi, Hyosung Lee, Hollie Swanson, and Kyung-Bo Kim*
The treatment of hormone-sensitive breast cancers often relies on estrogen receptor (ER) antagonists. In spite of initial response to such drugs, ER-positive breast cancer cells eventually become resistant; in most cases, the ER continues to regulate tumor growth.
Kim and colleagues have taken a Trojan-horse approach in targeting the ER for degradation by using proteolysis targeting chimeras (PROTACs). These consist of estradiol conjugated through a linker to a pentapeptide motif, which is recognized by E3 ubiquitin ligase; subsequent ubiquitination marks the ER for proteolytic degradation. In this work, they further refined their PROTAC approach, determining the optimal configuration for ER recognition of the estradiol ligand and subsequent ubiquitination. Marking the ER for proteolysis represents a new angle on combating drug resistance in breast cancer cells.
Received April 7, 2010; published online June 10, 2010, DOI: 10.1002/cmdc.201000146.