Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation
| Autor: | Floriane Braun, Olaf Kinzel, Simon Anderhub, Martin Hornberger, Gerald Kleymann, Barbara Morschhaeuser, Thomas J. Hoffmann, Sheena Pinto, Christoph Steeneck |
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| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
010405 organic chemistry Chemistry medicine.medical_treatment Organic Chemistry Glucuronidation Cancer Pharmacology medicine.disease 01 natural sciences Biochemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Cancer immunotherapy Drug Discovery medicine Pharmacophore Glucuronide ADME |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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 IC(50) 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). |
| Databáze: | OpenAIRE |
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