Discovery and Optimization of Novel Apo-IDO1 Inhibitors by a Pharmacophore-Based Structural Simplification Strategy

Indoleamine 2,3-dioxygenase-1 (IDO1) plays a crucial role in tumor immune escape. However, the limited clinical efficacy of traditional IDO1 inhibitors has impeded their further development. Recently, apo-IDO1 inhibitors that displace the heme to target IDO1 have been discovered, which exhibits a slow dissociation rate reminiscent of irreversible inhibitors. This characteristic suggests sustained target engagement, offering a pharmacodynamic advantage. Therefore, the development of apo-IDO1 inhibitors emerges as a promising strategy in the field of IDO1-related studies. Here, we present the identification of the thienopyrimidine derivative <b>XW-001</b> through structure-based virtual screening, followed by an iterative optimization process that led to the development of <b>XW-032</b>. <b>XW-032</b> exhibited remarkable <i>in vitro</i> inhibitory activity against apo-IDO1 (IC₅₀ = 21 ± 5 nM) through a pharmacophore-guided structural simplification approach. Notably, <b>XW-032</b> (TGI = 63%) exhibited potent <i>in vivo</i> antitumor efficacy in the CT26 syngeneic mouse model, highlighting the benefits of apo-IDO1 inhibitors for tumor immunotherapy.