Abstract 4877: Discovery of novel and potent inhibitors of indoleamine-2,3-dioxygenase (IDO1) for cancer immunotherapy

Indoleamine-2,3-dioxygenase (IDO1) is an immune regulatory enzyme that oxidizes tryptophan to kynurenine. IDO1 is overexpressed in numerous tumor cells that block T-cell activation, induce T-cell apoptosis and increase regulatory T cells, which create an environment in which tumor-specific cytotoxic T lymphocytes are no longer able to attack a patient's cancer cells. IDO1 inhibition reverses the immune suppression at the tumor site and allows the generation of an effective anticancer immune response. Preclinical and clinical studies have shown that IDO1 inhibitors increase the anticancer immune response and dramatically increase the efficacy of various therapeutic agents especially the immune checkpoint antibodies targeting PD-1, PD-L1 and CTLA-4. Via structure-based design, we have discovered a series of novel and potent IDO1 inhibitors that demonstrate strong IDO1 on-target activity with IC50 values ranging from 10 nM to 50 nM against human IDO1 enzyme. These compounds potently inhibit IDO1 in tumor-bearing mice as well as in Hela cells with lower single-digit to lower double digit nM IC50. The lead compound selected for clinical development shows good ADME profile, low serum binding, and good efficacy in various murine animal models when dosed orally and subcutaneously alone or in combination with immune checkpoint inhibitors. Preclinical evaluation of the compound will be presented in details. Citation Format: Shengyang Liu, Taoliangshan Tao, Yue Liang, Hongli Guo, Xiaogang Ye, Zhiheng Wu, Fang Bao, Heping Yang, Yaxian Cai, Gangjing Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Xiaolei Liu, Jiangang Du, Ping Qin, Yuanfei Ma, Panhu Zhu, Yajun Yu, Chen Ma, Pei Wang, Liping Zhao, Yuxun Wang, Daxin Gao, Qun Li. Discovery of novel and potent inhibitors of indoleamine-2,3-dioxygenase (IDO1) for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4877.