Discovery of novel IDO1 inhibitors targeting the protein's apo form through scaffold hopping from holo-IDO1 inhibitor.

Immunomodulating enzyme IDO1 plays an important role in tumor immune resistance. Inhibiting IDO1 by small molecules with new mechanism of action is a potential strategy in IDO1 inhibitor development. Based on our urea derived compound originally binding with holo-IDO1, through scaffold hopping, a series of diisobutylaminophenyl hydroxyamidine compounds were designed. Unexpectedly, this novel class of IDO1 inhibitor does not target the holo form of IDO1 protein but displaces heme and binds to its apo form. Representative compound I-4 exhibits moderate potency with IC50 value of 0.44 µM in cell-based IDO1 assay, which has the potential to be developed for IDO1-related cancer treatment.