Abstract 2736: Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the degradation of the essential amino acid L-tryptophan to kynurenine. It plays an important role in the initial and rate-limiting step in the breakdown of tryptophan. It has been reported that IDO1, an enzyme induced by IFN-gamma, is one of the central regulators of immune responses in various physiologic and pathologic settings and the enzyme is frequently expressed in cancers. Kynurenine produced by IDO1 suppresses T-cell function in the tumor microenvironment, resulting in tumor cell evasion from immune cells. IDO1 inhibitors, such as epacadostat and BMS-986205, have shown preliminary clinical therapeutic response in melanoma and other solid tumors when combined with anti-PD-1 antibody. Here, we report the discovery of a novel and selective IDO1 inhibitor with potent activity in various cell-based assays. Our lead molecule D-0751 inhibits IDO1 activity in HeLa cell and human whole blood assay with IC50 of 0.6 nM and 13 nM, respectively. It activates the human T-cell activity in a HeLa co-culture study with EC50 at 9 nM. D-0751 is optimized to have good PK profile in rodent, dog and monkey as well as slow clearance when incubated with human hepatocyte. Pharmacodynamic (PD) effect has been observed in mouse models (blood and tumor samples) as well as in dog (blood samples) with efficient kynurenine reduction observed at optimal dose level. Taken together, these results support the advancement of D-0751 as a clinical candidate in combination with anti-PD-1/L1 antibody in various solid tumor indications. Citation Format: Yaolin Wang, Zhe Shi, Zixing Han, Zhenwu Wang, Yueheng Jiang, Xing Dai. Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2736.