Unique Sulfur–Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors

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.