Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer.
Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer.
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DOI：
10.1002/cmdc.201600238
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发表时间：
2016-09-20
期刊：
影响因子：
3.4
通讯作者：
Callahan BP
中科院分区：
文献类型：
--
作者：
Bordeau BM;Ciulla DA;Callahan BP
阿比特龙是一种有效的人酶CYP 17 A1（细胞色素P450 c17）抑制剂，为晚期前列腺癌的异位雄激素生成提供了最后一道防线。在此，我们报告了阿比特龙和致癌刺猬蛋白之间前所未有的脱靶相互作用。我们的实验表明，阿比特龙及其结构同源物galeterone可以取代胆固醇作为hedgehog蛋白的专门生物合成事件（称为胆固醇溶解）中的底物。脱靶反应产生共价刺猬-药物缀合物。基于细胞的报告基因测定表明，这些缀合物在低纳摩尔范围内存在时激活hedgehog信号传导。由于刺猬信号传导与前列腺癌进展有关，并且阿比特龙被施用以治疗疾病的晚期，因此这种脱靶相互作用可能具有治疗意义。走错路了生物化学实验表明，甾体抗雄激素、阿比特龙和galeterone与hedgehog蛋白发生脱靶共价反应，产生hedgehog-药物缀合物。基于细胞的测定表明，这些缀合物在低纳摩尔范围内刺激刺猬信号传导。
Abiraterone, a potent inhibitor of the human enzyme CYP17A1 (cytochrome P450c17), provides a last line of defense against ectopic androgenesis in advanced prostate cancer. Herein we report an unprecedented off-target interaction between abiraterone and oncogenic hedgehog proteins. Our experiments indicate that abiraterone and its structural congener, galeterone, can replace cholesterol as a substrate in a specialized biosynthetic event of hedgehog proteins, known as cholesterolysis. The off-target reaction generates covalent hedgehog–drug conjugates. Cell-based reporter assays indicate that these conjugates activate hedgehog signaling when present in the low nanomolar range. Because hedgehog signaling is implicated in prostate cancer progression, and abiraterone is administered to treat advanced stages of the disease, this off-target interaction may have therapeutic significance. Wrong way! Biochemical experiments indicate that steroidal anti-androgens, abiraterone and galeterone, undergo off-target covalent reactions with hedgehog proteins to produce hedgehog– drug conjugates. Cell-based assays indicate that these conjugates stimulate hedgehog signaling in the low nanomolar range.
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影响因子：
64.8
作者：
Li Z;Bishop AC;Alyamani M;Garcia JA;Dreicer R;Bunch D;Liu J;Upadhyay SK;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
3.9
作者：
Ciepla, Paulina;Magee, Anthony I.;Tate, Edward W.
通讯作者：
Tate, Edward W.
DOI：
10.1083/jcb.201008090
发表时间：
2011-03-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
Salic A
影响因子：
37.3
作者：
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影响因子：
4.8
作者：
Buglino, John A.;Resh, Marilyn D.
通讯作者：
Resh, Marilyn D.