6V7F

Human Arginase1 Complexed with Bicyclic Inhibitor Compound 13

Summary for 6V7F

• Entry DOI: 10.2210/pdb6v7f/pdb
• Descriptor: Arginase-1, MANGANESE (II) ION, {3-[(5R,7S,8S)-8-azaniumyl-8-carboxy-2-azaspiro[4.4]nonan-2-ium-7-yl]propyl}(trihydroxy)borate(1-), ... (4 entities in total)
• Functional Keywords: agonist, arg (arginase), bicyclic, immunotherapy, metalloenzyme, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 211073.47

Authors

Palte, R.L.,Lesburg, C.A. (deposition date: 2019-12-08, release date: 2020-05-06, Last modification date: 2023-10-11)

Primary citation

Mitcheltree, M.J.,Li, D.,Achab, A.,Beard, A.,Chakravarthy, K.,Cheng, M.,Cho, H.,Eangoor, P.,Fan, P.,Gathiaka, S.,Kim, H.Y.,Lesburg, C.A.,Lyons, T.W.,Martinot, T.A.,Miller, J.R.,McMinn, S.,O'Neil, J.,Palani, A.,Palte, R.L.,Sauri, J.,Sloman, D.L.,Zhang, H.,Cumming, J.N.,Fischer, C.
Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.
Acs Med.Chem.Lett., 11:582-588, 2020

PubMed Abstract: 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, , 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.

PubMed: 32292567
DOI: 10.1021/acsmedchemlett.0c00058

Experimental method

X-RAY DIFFRACTION (2.02 Å)