Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.

中文翻译：

---

独特的硫-芳烃相互作用有助于强效咪唑并噻唑吲哚胺 2,3-双加氧酶抑制剂的结合。

吲哚胺 2,3-双加氧酶 (IDO1) 抑制剂被推测可用于癌症免疫治疗，但最先进的 IDO1 抑制剂 epacadostat 的 III 期临床试验未达到其主要终点并被放弃。在之前的工作中，我们确定了新型 IDO1 抑制剂 N-(4-氯苯基)-2-((5-苯基噻唑并[2,3-c][1,2,4]三唑-3-基)硫代)乙酰胺 1 到高通量筛选 (HTS)。在此，我们报告了该化合物的构效关系 (SAR) 研究，该研究产生了有效的 IDO1 抑制剂 1-(4-氰基苯基)-3-(3-(环丙基乙炔基)咪唑并[2,1-b]噻唑- 5-基)硫脲 47 (hIDO IC50 = 16.4 nM)。X 射线共晶结构分析表明，这种高效能的基础是由 47 的硫脲部分与 F163 和 F226 形成的独特的硫-芳烃相互作用网络。