Schneekloth Ashley R, Pucheault Mathieu, Tae Hyun Seop, Crews Craig M
Department of Chemistry, Yale University, PO Box 208103, New Haven, CT 06520-8103, USA.
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5904-8. doi: 10.1016/j.bmcl.2008.07.114. Epub 2008 Jul 31.
We have developed a heterobifunctional all-small molecule PROTAC (PROteolysis TArgeting Chimera) capable of inducing proteasomal degradation of the androgen receptor. This cell permeable PROTAC consists of a non-steroidal androgen receptor ligand (SARM) and the MDM2 ligand known as nutlin, connected by a PEG-based linker. The SARM-nutlin PROTAC recruits the androgen receptor to MDM2, which functions as an E3 ubiquitin ligase. This leads to the ubiquitination of the androgen receptor, and its subsequent degradation by the proteasome. Upon treatment of HeLa cells with 10microM PROTAC for 7h, we were able to observe a decrease in androgen receptor levels. This degradation is proteasome dependent, as it is mitigated in cells pre-treated with 10microM epoxomicin, a specific proteasome inhibitor. These results have implications for the potential study and treatment of various cancers with increased androgen receptor levels.
我们开发了一种异双功能全小分子PROTAC（蛋白酶靶向嵌合体），它能够诱导雄激素受体的蛋白酶体降解。这种可穿透细胞的PROTAC由一种非甾体雄激素受体配体（SARM）和一种名为nutlin的MDM2配体组成，通过基于聚乙二醇的连接子相连。SARM-nutlin PROTAC将雄激素受体招募至MDM2，MDM2作为一种E3泛素连接酶发挥作用。这导致雄激素受体的泛素化，随后其被蛋白酶体降解。用10微摩尔的PROTAC处理HeLa细胞7小时后，我们能够观察到雄激素受体水平的下降。这种降解依赖于蛋白酶体，因为在用10微摩尔的环氧霉素（一种特异性蛋白酶体抑制剂）预处理的细胞中，这种降解作用会减弱。这些结果对研究和治疗雄激素受体水平升高的各种癌症具有潜在意义。
