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Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Down-regulators

雌激素受体 受体 子类 选择性雌激素受体调节剂 化学 癌症研究 药理学 生物 生物化学 癌症 内科学 医学 乳腺癌 抗体 遗传学
作者
Bryan M. Wittmann,Andrea B. Sherk,Donald P. McDonnell
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:67 (19): 9549-9560 被引量:120
标识
DOI:10.1158/0008-5472.can-07-1590
摘要

Abstract One subclass of antiestrogens, the selective estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit estrogen binding and induce a rapid, proteasome-dependent degradation of the receptor. Contained within this class of molecules is the steroidal antiestrogen ICI182,780 (faslodex), recently approved for the treatment of metastatic cancer, and GW5638/DPC974, a SERD that is currently being evaluated in the clinic. Given that mechanistic differences between different selective estrogen receptor modulators have been translated into important clinical profiles, it was of interest to determine if the SERD subclass of ligands were likewise functionally or mechanistically distinguishable. In this study, we show that although the steroidal and nonsteroidal SERDs target ERα for degradation, the underlying mechanism(s) are different. Of note was the identification of a specific protein-protein interaction surface presented on ERα in the presence of the ICI182,780-activated receptor which is required for degradation. Interestingly, this surface is also presented on ERα in the presence of RU58,668, a SERD that is chemically distinct from ICI182,780. This surface is not required for GW5638-mediated degradation, and thus, this SERD seems to affect ERα down-regulation by a different mechanism. These data suggest that sequencing of therapies using drugs of this class is likely to be possible. Finally, because of the unmet need for orally active SERDS that function similarly to ICI182,780, we have used the insights from these mechanistic studies to develop and validate a high-throughput screen for compounds of this class with improved pharmaceutical properties. [Cancer Res 2007;67(19):9549–60]

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