Masoodi Khalid Z, Eisermann Kurtis, Yang Zhenyu, Dar Javid A, Pascal Laura E, Nguyen Minh, O'Malley Katherine, Parrinello Erica, Feturi Firuz G, Kenefake Alex N, Nelson Joel B, Johnston Paul A, Wipf Peter, Wang Zhou
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232.
Transcriptomics Laboratory, Division of Plant Biotechnology, SKUAST-Kashmir, Shalimar, Srinagar, Jammu and Kashmir 190025, India.
Endocrinology. 2017 Oct 1;158(10):3152-3161. doi: 10.1210/en.2017-00408.
The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide.
雄激素受体（AR）在去势抵抗性前列腺癌（CRPC）的发展以及对第二代AR拮抗剂恩杂鲁胺和细胞色素P450 17A1（CYP17A1）选择性抑制剂阿比特龙的耐药性中起着关键作用。靶向AR的新型药物可能会抑制对恩杂鲁胺和/或阿比特龙耐药的前列腺癌细胞的生长。通过对一个包含220,000个成员的小分子文库进行高通量/高内涵筛选，我们之前已鉴定出2-[(异恶唑-4-基甲基)硫代]-1-(4-苯基哌嗪-1-基)乙酮（IMTPPE）（SID 3712502）是一种能够抑制C4-2前列腺癌细胞中AR转录活性和蛋白水平的新型小分子。在本研究中，我们通过实时聚合酶链反应、蛋白质印迹和荧光素酶测定表明IMTPPE可抑制AR靶基因表达。IMTPPE抑制培养中AR阳性而非AR阴性前列腺癌细胞的增殖。IMTPPE抑制了缺乏配体结合域（LBD）的突变型AR的转录活性，表明IMTPPE对AR的抑制作用不依赖于LBD。此外，动物研究表明IMTPPE可抑制22Rv1异种移植瘤的生长，22Rv1异种移植瘤是恩杂鲁胺耐药前列腺癌的一个模型。这些发现表明IMTPPE是开发用于治疗CRPC（包括对恩杂鲁胺耐药的CRPC）临床候选药物的潜在先导化合物。
