7KLL

Human Arginase1 Complexed with Inhibitor Compound 18

7KLL の概要

• エントリーDOI: 10.2210/pdb7kll/pdb
• 分子名称: 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)
• 機能のキーワード: arginase, hydrolase, urea cycle, metabolism, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 210736.83

構造登録者

Palte, R.L. (登録日: 2020-10-30, 公開日: 2021-09-29, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.22 Å)