近日,我院秦冲教授团队在靶向雄激素受体(AR)的小分子降解剂研究领域连续取得新进展,在国际药物化学领域顶级期刊 《Journal of Medicinal Chemistry》上发表两篇研究性论文。 一、热休克蛋白90(Heat shock protein 90,Hsp90)是真核生物中一种非常重要的蛋白质。研究发现,肿瘤细胞中的Hsp90表达水平会异常升高,并发挥重...
The NTD domain accounts for more than half of the entire AR protein as in Fig. 2 (amino acids 1–558). AR NTD contains polyglutamine (ploy-Q) and polyglycine (poly-G) repeats, and the length of these two repeats is highly variable in the human population43,44. The latest human AR ...
The full-length AR is comprised of eight exons (a) which make up the amino-terminal domain (NTD), the DNA-binding domain (DBD), a hinge region, and the carboxy-terminal ligand-binding domain (LBD). The ARv7—also known as AR3—contains exons 1–3 (b), comprising the NTD and the...
研究背景在该工作中,中国海洋大学秦钟课题组报告了靶向雄激素受体N末端结构域(AR-NTD)的小分子PROTAC化合物,通过连接子将AR-NTD拮抗剂和不同类别的E3连接酶配体栓系而获得。代表性化合物BWA-522有效地诱导AR-FL和AR-V7的降解,并且在体外比相应的拮抗剂更有效地对抗前列腺癌(PC)细胞。其研究结果证明BWA-522降解...
研究人员选择AR-NTD拮抗剂EPI-002作为靶蛋白配体,E3连接酶VHL与CRBN的配体作为招募E3配体,通过不同Linker将两部分连接。通过降解活性初筛,BWA-522被作为候选分子进行接下来的研究。在随后PK测试中,研究人员发现化合物BWA-522具有良好的口服血浆暴露,AUC值为5947 h·ng/ml,且口服生物利用度为40.5%。鉴于BWA-522在小...
However, we recently demonstrated that EPI-7386, an AR NTD small molecule inhibitor, inhibits AR activity by binding to Tau5 region of the NTD. By developing an aniten based bifunctional degrader (ANITAC for ANITen bAsed Chimera), our goal is to eliminate any forms of AR protein found in...
3D). Ectopic expression of the VP16 AD-AR NTD fusion protein in the absence of the GAL4 DBD-Sam68 fusion protein did not affect reporter activity. However, in the presence of the GAL4 DBD-Sam68 fusion protein, ectopic expression of the AR NTD fusion protein resulted in ~1.7-fold ...
雄激素受体由4个结构域和8个外显子组成,依次为 N-端结合域(NTD、外显子1)、 DNA 结合域(DBD、外显子2-3)、铰链区(HR、外显子4)、C-端结合域(LBD、外显子5-8),核定位信号(NLS)是包含在外显子3和4内的一个二分基序。 LBD 包含一个埋藏激素结合口袋(HBP)和1个转录激活功能区域 AF2。AF2在同源...
Color squares symbols different domains of AR protein. NTD: N-terminal domain; DBD: DNA binding domain; HR: hinge region; LBD: ligand binding domain. (D) Testicular histopathology of H&E staining from the proband indicated the total absence of germline cells in seminiferous tubules, conformed ...
The results showed that ectopic AR–FL or AR–NTD truncation mutant formed protein complexes with endogenous YAP1 (Fig. 5c, lane 2, 3, respec- tively). The HA-vector produces a very small peptide, which cannot be detected under these experimental conditions, possibly due to running off the...