Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy

Matthew J. Mitcheltree, Derun Li, Abdelghani Achab, Adam Beard, Kalyan Chakravarthy, Mangeng Cheng, Hyelim Cho, Padmanabhan Eangoor, Peter Fan, Symon Gathiaka, Hai-Young Kim, Charles A. Lesburg, Thomas W. Lyons, Theodore A. Martinot, J. Richard Miller, Spencer McMinn, Jennifer O'Neil, Anandan Palani, Rachel L. Palte, Josep SauriDavid L. Sloman, Hongjun Zhang, Jared N. Cumming, Christian Fischer

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Resum

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 enzymeinhibitor 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.
Idioma originalAnglès
Pàgines (de-a)582-588
Nombre de pàgines7
RevistaAcs Medicinal Chemistry Letters
Volum11
Número4
DOIs
Estat de la publicacióPublicada - 9 d’abr. 2020
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