Send to

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

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

Author information

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


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).

[Available on 2021-02-13]

Conflict of interest statement

The authors declare no competing financial interest.

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center