Unique Sulfur–Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors
Yi‐Hui Peng, Fang-Yu Liao, Chen‐Tso Tseng, Ramajayam Kuppusamy, An-Siou Li, Chi-Han Chen, Yu-Shiou Fan, Sing-Yi Wang, Mine-Hsine Wu, Ching-Cheng Hsueh, Jia-Yu Chang, Lung-Chun Lee, Chuan Shih, Kak‐Shan Shia, Teng‐Kuang Yeh, Ming‐Shiu Hung, Ching‐Chuan Kuo, Jen‐Shin Song, Su‐Ying Wu, Shau‐Hua Ueng
Abstract
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 IC 50 = 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.