8E5N

Structure of ARG1 complex with pyrrolidine-based non-boronic acid inhibitor 10

Summary for 8E5N

• Entry DOI: 10.2210/pdb8e5n/pdb
• Descriptor: Arginase-1, MANGANESE (II) ION, 1-{[(3S,4S)-3-(3-fluorophenyl)-4-{[4-(1,3,4-triethyl-1H-pyrazol-5-yl)piperidin-1-yl]methyl}pyrrolidin-1-yl]methyl}cyclopentane-1-carboxylic acid, ... (4 entities in total)
• Functional Keywords: arginase, arginine metabolism, urea cycle, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 212570.97

Authors

Palte, R.L.,Gathiaka, S. (deposition date: 2022-08-22, release date: 2023-03-08, Last modification date: 2023-10-25)

Primary citation

Gathiaka, S.,Palte, R.L.,So, S.S.,Chai, X.,Richard Miller, J.,Kuvelkar, R.,Wen, X.,Cifelli, S.,Kreamer, A.,Liaw, A.,McLaren, D.G.,Fischer, C.
Discovery of non-boronic acid Arginase 1 inhibitors through virtual screening and biophysical methods.
Bioorg.Med.Chem.Lett., 84:129193-129193, 2023

PubMed Abstract: Inhibiting Arginase 1 (ARG1), a metalloenzyme that hydrolyzes l-arginine in the urea cycle, has been demonstrated as a promising therapeutic avenue in immuno-oncology through the restoration of suppressed immune response in several types of cancers. Most of the currently reported small molecule inhibitors are boronic acid based. Herein, we report the discovery of non-boronic acid ARG1 inhibitors through virtual screening. Biophysical and biochemical methods were used to experimentally profile the hits while X-ray crystallography confirmed a class of trisubstituted pyrrolidine derivatives as optimizable alternatives for the development of novel classes of immuno-oncology agents targeting this enzyme.

PubMed: 36822300
DOI: 10.1016/j.bmcl.2023.129193

Experimental method

X-RAY DIFFRACTION (2.538 Å)