NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been associated with a number of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to technical challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2. As such, RIPK2 represents an attractive target to probe the pathological roles of NOD2 pathway. To search for selective RIPK2 inhibitors, we employed virtual library screening (VLS) and structure based design that eventually led to a potent and selective RIPK2 inhibitor 8 with excellent oral bioavailability, which was used to evaluate the effects of inhibition of RIPK2 in various in vitro assays and ex vivo and in vivo pharmacodynamic models.

中文翻译：

---

鉴定有效和选择性的RIPK2抑制剂来治疗炎性疾病

NOD2（含有核苷酸结合的寡聚域的蛋白质2）是一种内部模式识别受体，可识别细菌肽聚糖并刺激宿主免疫反应。NOD2通路功能障碍与许多自身炎症性疾病有关。迄今为止，由于靶向寡聚蛋白复合物的技术挑战，尚未描述NOD2的直接抑制剂。受体相互作用蛋白激酶2（RIPK2）是细胞内丝氨酸/苏氨酸/酪氨酸激酶，是关键的信号传导伴侣，也是NOD2的专一性激酶。因此，RIPK2代表了一个有吸引力的靶标，以探索NOD2途径的病理作用。为了寻找选择性的RIPK2抑制剂，我们采用了虚拟文库筛选（VLS）和基于结构的设计，最终导致了有效而选择性的RIPK2抑制剂8具有优异的口服生物利用度，用于评估RIPK2在各种体外测定以及离体和体内药效学模型中的抑制作用。