Kallen Joerg, Izaac Aude, Be Celine, Arista Luca, Orain David, Kaupmann Klemens, Guntermann Christine, Hoegenauer Klemens, Hintermann Samuel
CBT, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
ChemMedChem. 2017 Jul 6;12(13):1014-1021. doi: 10.1002/cmdc.201700278. Epub 2017 Jun 20.
The T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-γ (RORγt) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORγt inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORγt agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co-crystallization with a co-activator peptide and helix 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORγt modulators.
T细胞特异性视黄酸受体（RAR）相关孤儿受体γ（RORγt）是促炎性Th17细胞因子产生的关键转录因子，这些细胞因子与自身免疫性疾病的发病机制有关。多年来，已经报道了几种结构多样的RORγt反向激动剂，但将高效能与良好的物理化学性质相结合仍然是一项具有挑战性的任务。我们最近报道了一系列基于咪唑并吡啶核心的新型反向激动剂，它们具有良好的物理化学性质和出色的选择性。在此，我们报告了不同类别的天然和合成化合物的八个新的X射线晶体结构，包括从专利文献中选取的实例。对它们各自结合模式的分析揭示了对导致激动、拮抗或反向激动的分子机制的深入了解。我们报告了RORγt激动的新分子机制，并提出将反向激动剂分为两类：一类通过空间冲突起作用，另一类通过其他机制起作用（对于后者，与共激活肽和处于激动剂位置的螺旋12共结晶仍然是可能的）。对于非空间冲突反向激动剂，我们提出了一种新机制（“水捕获”），它可以与其他机制（例如，与H479紧密接触）相结合。此外，我们比较了在S404附近的“后口袋”和R364和R367附近的“硫酸盐口袋”中选定化合物的相互作用。综上所述，这些新的机制见解应该对进一步设计和优化RORγt调节剂有用。
