Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , Miaoli County 35053 , Taiwan.
School of Pharmacy , National Cheng Kung University , Tainan 70101 , Taiwan.
J Med Chem. 2020 Feb 27;63(4):1642-1659. doi: 10.1021/acs.jmedchem.9b01549. Epub 2020 Feb 10.
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 -(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-][1,2,4]triazol-3-yl)thio)acetamide 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-]thiazol-5-yl)thiourea (hIDO IC = 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 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.
吲哚胺 2,3-双加氧酶 (IDO1) 抑制剂被推测在癌症免疫治疗中有用，但最先进的 IDO1 抑制剂 epacadostat 的 III 期临床试验未达到主要终点并被放弃。在之前的工作中，我们通过高通量筛选 (HTS) 鉴定了新型 IDO1 抑制剂 -(4-氯苯基)-2-((5-苯基噻唑并[2,3-][1,2,4]三唑-3-基)硫代)乙酰胺。在此，我们报告了该化合物的构效关系 (SAR) 研究，该研究导致了强效 IDO1 抑制剂 1-(4-氰基苯基)-3-(3-(环丙基乙炔基)咪唑并[2,1-]噻唑-5-基)硫脲 (hIDO IC = 16.4 nM)。X 射线共晶结构分析表明，这种高效力的基础是硫脲部分与 F163 和 F226 形成的独特的硫-芳族相互作用网络。这一发现有望为未来发现强效 IDO1 抑制剂提供新的方法。
