7KLL

Human Arginase1 Complexed with Inhibitor Compound 18

Summary for 7KLL

• Entry DOI: 10.2210/pdb7kll/pdb
• Descriptor: Arginase-1, MANGANESE (II) ION, 3-[(2~{S},3~{R},4~{R})-4-azanyl-2-carboxy-pyrrolidin-3-yl]propyl-$l^{3}-oxidanyl-bis(oxidanyl)boron, ... (4 entities in total)
• Functional Keywords: arginase, hydrolase, urea cycle, metabolism, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 210736.83

Authors

Palte, R.L. (deposition date: 2020-10-30, release date: 2021-09-29, Last modification date: 2023-10-18)

Primary citation

Lu, M.,Zhang, H.,Li, D.,Childers, M.,Pu, Q.,Palte, R.L.,Gathiaka, S.,Lyons, T.W.,Palani, A.,Fan, P.W.,Spacciapoli, P.,Miller, J.R.,Cho, H.,Cheng, M.,Chakravarthy, K.,O'Neil, J.,Eangoor, P.,Beard, A.,Kim, H.Y.,Sauri, J.,Gunaydin, H.,Sloman, D.L.,Siliphaivanh, P.,Cumming, J.,Fischer, C.
Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.
Acs Med.Chem.Lett., 12:1380-1388, 2021

PubMed Abstract: Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors , , and , demonstrated a favorable overall profile, and was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.

PubMed: 34527178
DOI: 10.1021/acsmedchemlett.1c00195

Experimental method

X-RAY DIFFRACTION (2.22 Å)