Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy
| Autor: | Matthew J. Mitcheltree, Theodore A. Martinot, Thomas W. Lyons, Spencer McMinn, Peter W. Fan, Hyelim Cho, Christian Fischer, Kalyan Chakravarthy, David L. Sloman, Padmanabhan Eangoor, Jared N. Cumming, Charles A. Lesburg, Mangeng Cheng, Adam Beard, Derun Li, Hongjun Zhang, Jennifer O'Neil, Abdelghani Achab, Rachel L. Palte, Anandan Palani, J. Richard Miller, Josep Saurí, Symon Gathiaka, Hai-Young Kim |
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| Rok vydání: | 2020 |
| Předmět: |
Tumor microenvironment
Arginine Bicyclic molecule 010405 organic chemistry medicine.medical_treatment Immune checkpoint inhibitors Organic Chemistry Ornithine Pharmacology 01 natural sciences Biochemistry 0104 chemical sciences Bioavailability Arginase 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry Cancer immunotherapy Drug Discovery medicine |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00058 |
| Popis: | [Image: see text] The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme–inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored. |
| Databáze: | OpenAIRE |
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