Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Eur J Med Chem. 2023 Oct 5;258:115574. doi: 10.1016/j.ejmech.2023.115574. Epub 2023 Jun 14.
The transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) is an attractive drug target for some autoimmune diseases owing to its roles in the differentiation of human T helper 17 (Th17) cells which produce pro-inflammatory cytokine interleukin (IL)-17. RORγt agonists and inverse agonists are classically targeted to the hydrophobic and highly conserved orthosteric binding pocket of RORγt ligand binding domain (LBD). Although successful, this approach also brings some challenges, including off-target effects due to lack of selectivity over other nuclear receptors (NRs). Allosteric regulation of RORγt by synthetic small molecules has recently emerged as novel research interests for its interesting modes of action (MOA), satisfying bioactivity profile and improved selectivity. In this review, we delineated the discovery and identification of the allosteric pocket of RORγt. Subsequently, we focused on examples of small molecules that allosterically inhibit RORγt, with a central attention on structural-activity-relationship (SAR) information, biological activity, pharmacokinetic (PK) property, and the ligand binding mode of these compounds. We also discussed the potential role of RORγt allosteric inverse agonists as small molecule therapeutics for autoimmune diseases.
转录因子维甲酸相关孤儿受体γt（RORγt）在人类辅助性 T 细胞 17（Th17）细胞的分化中发挥作用，可产生促炎细胞因子白细胞介素（IL）-17，因此成为一些自身免疫性疾病有吸引力的药物靶点。RORγt 激动剂和反向激动剂通常靶向 RORγt 配体结合域（LBD）的疏水且高度保守的正位结合口袋。尽管这种方法取得了成功，但也带来了一些挑战，包括由于缺乏对其他核受体（NR）的选择性而产生的脱靶效应。合成小分子对 RORγt 的别构调节最近成为新的研究兴趣，因为其具有有趣的作用模式（MOA）、满足生物活性特征和提高的选择性。在这篇综述中，我们阐述了 RORγt 别构口袋的发现和鉴定。随后，我们重点介绍了一些别构抑制 RORγt 的小分子的例子，重点关注结构-活性关系（SAR）信息、生物活性、药代动力学（PK）特性以及这些化合物的配体结合模式。我们还讨论了 RORγt 别构反向激动剂作为自身免疫性疾病小分子治疗药物的潜在作用。
