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Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy
journal contribution
posted on 2020-03-25, 13:42 authored by 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 Saurí, David L. Sloman, Hongjun Zhang, Jared N. Cumming, Christian FischerThe 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.
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arginine elevationimmune-cell activitynovel inhibitorsactive-transport recognition motifscheckpoint inhibitorsBicyclic Inhibitorsscaffold modificationbioavailabilityserum arginase inhibitionHuman Arginasetumor microenvironmentsyngeneic mouse carcinoma modelStructure-based design strategiesEnhance Cancer Immunotherapy
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