ChemMedChem

Cover image for Vol. 11 Issue 10

Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)

Impact Factor: 2.968

ISI Journal Citation Reports © Ranking: 2014: 19/59 (Chemistry Medicinal); 83/255 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

June 15, 2010

VIP: Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor-Targeting PROTACs

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.

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