Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
Molecules. 2018 Nov 14;23(11):2967. doi: 10.3390/molecules23112967.
Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40⁻50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.
孤儿核受体 TLX（NR2E1）在神经干细胞（NSC）的调节以及 NSC 衍生的脑肿瘤的发展中起着关键作用。在过去的几年中，有新的数据表明 TLX 与前列腺癌和乳腺癌有关。因此，TLX 转录活性的抑制剂可能对几种严重癌症的治疗有重大影响。然而，TLX 蛋白具有非典型的配体结合域（LBD），该结构缺乏配体结合口袋（通常针对核受体进行靶向），这使得 TLX 的小分子抑制剂的开发变得复杂。在此，我们利用合理的基于结构的设计方法来鉴定靶向人 TLX LBD 的 Atro-box 结合位点的小分子。通过对约 700 万个分子结构的虚拟筛选，鉴定出 97 种化合物，并在 TLX 反应性荧光素酶报告基因测定中进行了评估。其中，有三种化学物质在 35µM 的剂量下，对 TLX 孤儿核受体的荧光素酶检测转录活性表现出 40-50%的抑制作用。所鉴定的化合物代表了通过计算机辅助药物发现方法鉴定的 TLX 转录活性的第一类小分子抑制剂。
