Abstract 3277: IACS-9779, a development candidate that inhibits 2,3-dioxygenase (IDO) activity by blocking heme incorporation into IDO apoenzyme

Abstract

Increased expression of IDO1 is believed to create a tumor microenvironment that is immunosuppressive. In the course of our research directed at identifying potent and selective inhibitors of IDO1, we identified a class of compounds that inhibited IDO1 activity in a cellular context, but not in isolated enzymatic assays. We have conducted detailed mechanistic studies and shown that these molecules inhibit IDO1 by binding to the apo-enzyme, thus preventing the incorporation of the heme-cofactor into the active site of the holo-enzyme. Through an extensive medicinal chemistry campaign, we optimized a series of orally bioavailable, highly potent and selective inhibitors of IDO1 that possess excellent pharmacological properties. For several lead molecules, pharmacokinetic (PK) - pharmacodynamic (PD) relationships were established in whole blood and SKOV3 xenograft assays. The inhibition of IDO1 in a human whole-blood assay correlated well with the suppression of tumor kynurenine (KYN) that was observed in SKOV3 xenografts. At plasma concentrations of 3 µM, IACS-9779 supressed tumor KYN levels by 90%. IACS-9779 was well tolerated with excellent in vivo PK properties across multiple preclinical species, and a human PK prediction consistent with a low daily dose needed for full suppression of KYN production via IDO1. Note: This abstract was not presented at the meeting. Citation Format: Faika Mseeh, Matthew M. Hamilton, Joseph R. Marszalek, Norma E. Rogers, Connor A. Parker, Simon S. Yu, Zhen Liu, Naphtali J. Reyna, Timothy McAfoos, Brett W. Virgin-Downey, Paul G. Leonard, Jason B. Cross, Ningping Feng, Angela L. Harris, Andy M. Zuniga, Keith Mikule, Martin Tremblay, Yongying Jiang, Mikhila Mahendra, Jihai Pang, Qi Wu, Quanyun Xu, Timothy P. Heffernan, Philip Jones, Richard T. Lewis. IACS-9779, a development candidate that inhibits 2,3-dioxygenase (IDO) activity by blocking heme incorporation into IDO apoenzyme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3277.

The Role of Metabolism in Tumor Immune Evasion: Novel Approaches to Improve Immunotherapy

“…Other molecules assessed in clinical trials that target IDO are Navoximod, DN1406131, EOS200271 (PF-06840003) [ 126 ], KHK2455, LY01013, MK-7162, SHR9146 (HTI-1090). Additionally, several preclinical studies with novel molecules targeting not only IDO1 but also IDO2 and TDO are being evaluated in cancer as a single agent: DN016 [ 127 ], EPL-1410 [ 128 ], IACS-9779 [ 129 ], RG70099 [ 130 ], TQBWX220 [ 131 ], CMG017 [ 132 ], STB-C017 [ 133 ], and in combination with immunotherapy: DN016 [ 127 ], CMG017, STB-C017 [ 95 , 96 ].…”