6v7d

Publication Abstract from PubMed

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.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.,Mitcheltree MJ, Li D, Achab A, Beard A, Chakravarthy K, Cheng M, Cho H, Eangoor P, Fan P, Gathiaka S, Kim HY, Lesburg CA, Lyons TW, Martinot TA, Miller JR, McMinn S, O'Neil J, Palani A, Palte RL, Sauri J, Sloman DL, Zhang H, Cumming JN, Fischer C ACS Med Chem Lett. 2020 Mar 23;11(4):582-588. doi:, 10.1021/acsmedchemlett.0c00058. eCollection 2020 Apr 9. PMID:32292567^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.