Discovery of potent IDO1 inhibitors derived from tryptophan using scaffold-hopping and structure-based design approaches

摘要

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e , 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells. Treatment with these three compounds promoted the proliferation of T lymphocyte and led to the dramatic decrease of regulatory T cells in the B16F1 cells and na?ve T cells co-culture system. Subsequent spectroscopic experiments suggested that these benzoxazolinones formed a coordinate bond with the heme iron to stabilize the complex. This study suggested that the benzoxazolinone was an interesting scaffold for discovering novel IDO1 inhibitors, and these compounds are attractive candidates for further development. Graphical abstract Display Omitted Highlights ? A scaffold-hopping strategy combined with the average electrostatic potentials calculation was utilized to design novel benzoxazolinone derivatives. ? A novel interesting scaffold for IDO1 inhibition was identified. ? T-cell proliferation and Tregs assays were performed to evaluate the capacity of the compounds in the reversal of IDO1-mediated immunosuppression. ? UV spectroscopic experiment provided a direct evidence of our compounds binding to the active site of IDO1. ? The induced fit docking and QM/MM calculation were performed to predict the binding mode of IDO1 and its ligand.