Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation

Christoph Steeneck; Olaf Kinzel; Simon Anderhub; Martin Hornberger; Sheena Pinto; Barbara Morschhaeuser; Floriane Braun; Gerald Kleymann; Thomas Hoffmann

doi:10.1021/acsmedchemlett.9b00572

Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation

ACS Med Chem Lett. 2020 Jan 27;11(2):179-187. doi: 10.1021/acsmedchemlett.9b00572. eCollection 2020 Feb 13.

Authors

Christoph Steeneck¹, Olaf Kinzel¹, Simon Anderhub¹, Martin Hornberger¹, Sheena Pinto¹, Barbara Morschhaeuser¹, Floriane Braun¹, Gerald Kleymann¹, Thomas Hoffmann¹

Affiliation

¹ Phenex Pharmaceuticals AG, Waldhofer Strasse 104, 69123 Heidelberg, Germany.

Abstract

Following the impressive success of checkpoint inhibitors in the treatment of cancer, combinations of IDO1 inhibitors with PD-1/PD-L1 antibodies are in clinical development aiming to increase response rates. Using the hydroxyamidine pharmacophore of the IDO1 inhibitor INCB14943 as a starting point for the design of new inhibitors, the potential shortcomings of extensive hydroxyamidine glucuronidation in humans was addressed. Compounds were optimized using a stability assay with recombinant UGT1A9 enzyme together with the measurement of glucuronide formation in human hepatocytes. Optimized analog 24 showed cellular and biochemical IDO1 IC₅₀ values in the low nanomolar range, a suitable in vitro ADME/PK profile, and efficacy in an animal model of cancer. In a humanized liver mouse model the lead compound exhibited significantly reduced glucuronidation compared to epacadostat (2).