Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs.
Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs.
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DOI：
10.1002/cmdc.201000146
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发表时间：
2010-07-05
期刊：
影响因子：
3.4
通讯作者：
Kim, Kyung-Bo
中科院分区：
文献类型：
--
作者：
Cyrus, Kedra;Wehenkel, Marie;Choi, Eun-Young;Lee, Hyosung;Swanson, Hollie;Kim, Kyung-Bo
雌激素受体-α（ER）拮抗剂已广泛用于乳腺癌治疗。尽管最初有反应，最终对ER敏感的ER阳性癌细胞对ER拮抗剂产生耐药性。已经表明，在大多数这些耐药肿瘤细胞中，ER表达并继续调节肿瘤生长。最近的研究表明，他莫昔芬最初作为拮抗剂，但后来作为ER激动剂，促进肿瘤生长。这表明靶向ER降解可能为乳腺癌提供有效的治疗方法，即使是那些对传统疗法有抵抗力的乳腺癌。考虑到这一点，我们先前证明PROTAC有效地诱导ER降解作为概念实验的证明。在此，我们进一步改进了PROTAC方法以靶向ER进行降解。ER靶向的PROTAC由一端的雌二醇和另一端的缺氧诱导因子1α（HIF-1α）衍生的合成五肽组成。五肽被称为von Hippel Lindau肿瘤抑制蛋白（pVHL）的E3泛素连接酶识别，从而将ER募集到E3连接酶中进行泛素化和降解。具体地，五肽连接在雌二醇上的三个不同位置以产生三种不同类型的PROTAC。当五肽通过雌二醇的C-7α位连接时，所得PROTAC显示出最有效的ER降解和对雌激素受体的最佳亲和力。该结果提供了开发新型ER拮抗剂的机会，其可以克服乳腺肿瘤对常规药物如他莫昔芬和氟维司群（Faslodex™）的耐药性。
Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, eventually hormone-sensitive ER-positive cancer cells develop resistance to ER antagonists. It has been shown that, in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies propose that tamoxifen initially acts as an antagonist but later functions as an ER agonist, promoting tumor growth. This suggests that targeted ER degradation may provide an effective therapeutic approach for breast cancers, even those which are resistant to conventional therapies. With this in mind, we previously demonstrated that PROTACs effectively induce degradation of the ER as a proof of concept experiment. Herein, we further refined the PROTAC approach to target the ER for degradation. The ER-targeting PROTACs are composed of an estradiol on one end and Hypoxia Inducing Factor 1α (HIF-1α)-derived synthetic pentapeptide on the other. The pentapeptide is recognized by an E3 ubiquitin ligase called the von Hippel Lindau tumor suppressor protein (pVHL), thereby recruiting the ER to this E3 ligase for ubiquitination and degradation. Specifically, the pentapeptide is attached at three different locations on estradiol to generate three different types of PROTACs. When the pentapeptide is linked through the C-7α position of estradiol, the resulting PROTAC showed the most effective ER degradation and best affinity for the estrogen receptor. This result provides an opportunity to develop a novel type of ER antagonist that may overcome the resistance of breast tumor to conventional drugs, such as tamoxifen and fulvestrant (Faslodex™).
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影响因子：
46.9
作者：
Jackson, AL;Bartz, SR;Linsley, PS
通讯作者：
Linsley, PS
影响因子：
56.9
作者：
Norris, JD;Paige, LA;McDonnell, DP
通讯作者：
McDonnell, DP
影响因子：
3.2
作者：
Lee, Hyosung;Puppala, Dinesh;Kim, Kyung-Bo
通讯作者：
Kim, Kyung-Bo
影响因子：
2.7
作者：
FEVIG T L;MAO M K;KATZENELLENBOGEN J A
通讯作者：
KATZENELLENBOGEN J A
影响因子：
4.8
作者：
JOHNSTON, JA;JOHNSON, ES;VARSHAVSKY, A
通讯作者：
VARSHAVSKY, A