"Identification and design of cancer immunotherapy agents" Prof. Su-Ying Wu

Cancer immunotherapy, a therapy to stimulate the patient’s immune system to attack the tumor cell, has provided a promising approach for the treatment of cancer. One of the mechanisms responsible for the escape of tumors from immune attack is through the tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). They are heme-containing enzymes that catalyze the initial and rate limiting step in the catabolism of tryptophan via the kynurenine pathway, leading to the formation of a series of biologically active metabolites. Through the catabolism of tryptophan, IDO/TDO inhibits the proliferation and differentiation of T cells, which are sensitive to the degradation of tryptophan and accumulation of tryptophan catabolites. A number of IDO inhibitors have been identified but only limited structural biology studies of IDO inhibitors are available to provide insights on the binding mechanism of IDO. We have recently solved the structures of IDO in complex with imidazoleisoindole derivatives, NLG919 (later named GDC-0919) analogues with potent activity. In this talk, structure-activity relationship, UV-spectra and structural biology studies of imidazoleisoindole derivaties will be presented and demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contributes to the great potency of this series of compounds.