Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11878-83. doi: 10.1073/pnas.1105160108. Epub 2011 Jul 5.
Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.
靶向雄激素受体 (AR) 新型表面和/或新型 AR 调节机制的药物是治疗去势抵抗性前列腺癌的有前途的替代方法。52 kDa FK506 结合蛋白 (FKBP52) 是细胞和整体动物模型中 AR 的重要正向调节剂，是治疗前列腺癌的有吸引力的靶标。我们使用改良的受体介导的酵母报告基因检测法筛选了多样化的天然化合物文库，以寻找抑制 FKBP52 增强 AR 功能的抑制剂。先导化合物称为 MJC13，通过防止热休克蛋白 90-FKBP52-AR 复合物的激素依赖性解离来抑制 AR 功能，从而导致核内结合的激素受体减少。在早期和晚期人前列腺癌细胞中的测定表明，MJC13 抑制 AR 依赖性基因表达和雄激素刺激的前列腺癌细胞增殖。
