5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as inhibitors of full-length RORγt
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as inhibitors of full-length RORγt
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5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物作为全长 ROR gamma t 抑制剂
DOI：
10.1016/j.bioorg.2019.103077
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发表时间：
2019-09-01
影响因子：
5.1
通讯作者：
Bai, Chuan
中科院分区：
文献类型：
--
作者：
Lao, Chuyu;Zhou, Xiaoqing;Bai, Chuan
类维生素A相关孤儿受体γ-t（ROR γ t）属于核受体超家族，在辅助性T细胞17（Th 17）的发育成熟和淋巴结发生中起重要作用。由于Th 17细胞已被证明是人类自身免疫性疾病和炎症性疾病的主要效应细胞，因此ROR γ t的激动剂和拮抗剂已被发现是这些疾病治疗的有希望的先导物。目前对ROR γ t抑制剂的研究主要集中在ROR γ t的配体结合结构域（LBD）上，因为LBD的结构和结合口袋已被详细阐明和研究。最近的研究阐明，ROR γ t的铰链结构域（HD）显著参与ROR γ t的SUMO化，从而特异性地影响T细胞发育，但不影响淋巴结发生。这些发现强调了ROR γ t HD作为ROR γ t抑制剂靶点的潜力，该抑制剂可以特异性抑制Th 17相关活性而不影响淋巴结发生。在这项研究中，我们利用了一个筛选系统与全长ROR γ t包括DBD，HD和LBD的四氢苯并[4，5]噻吩并[2，3-d]嘧啶衍生物的合成库的活性进行评估。我们鉴定了有效抑制Th 17细胞分化的有效先导化合物（28）。对接和构效关系（SAR）研究表明，化合物28可能不像大多数已知抑制剂那样结合在结合口袋中，但可能结合在HD中靠近Gln 223和Leu 244的口袋中。我们的研究表明，ROR γ t的HD可以提供一个Th 17特异性抑制剂的结合口袋，这一领域应进一步研究，以发现有效和特异性的ROR γ t抑制剂。
Retinoid-related orphan receptor gamma-t (ROR gamma t) belongs to the nuclear receptor superfamily that takes vital roles in the development and maturation of T-helper 17 cell (Th17) and lymph-node genesis. Because Th17 cells have been proved to be major effectors in human autoimmune and inflammatory diseases, the agonists and antagonists of ROR gamma t have been discovered as promising leads for the therapeutics of these diseases. Most of the current studies of ROR gamma t inhibitors have been focused on ligand binding domain (LBD) of ROR gamma t because the structure and binding pockets of LBD have been elucidated and studied in detail. Recent research elucidated that the hinge domain (HD) of ROR gamma t was significantly involved in the SUMOylation of ROR gamma t and thus specifically affecting T cell development but not lymph-node genesis. These discoveries highlighted the potential of HD of ROR gamma t as the target of ROR gamma t inhibitors that could specifically inhibit Th17-related activities without affecting lymph-node genesis. In this study, we utilized a screening system with full-length ROR gamma t including DBD, HD and LBD to evaluate the activities of a synthesized library of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. We identified a potent lead compound (28) that effectively inhibited Th17 cell differentiation. Docking and structure-activity relationship (SAR) studies showed that compound 28 may not bind in the binding pocket as most of the known inhibitors, but may bind in the pocket closed to Gln223 and Leu244 in HD. Our studies showed evidence that the HD of ROR gamma t could afford a binding pocket for Th17 specific inhibitors and this domain should be further studied to discover potent and specific ROR gamma t inhibitors.