8RFA

Arginase 2 in complex with an inhibitor

これはPDB形式変換不可エントリーです。

8RFA の概要

• エントリーDOI: 10.2210/pdb8rfa/pdb
• 分子名称: Arginase-2, mitochondrial, MANGANESE (II) ION, [(4~{R},5~{S})-4-(aminomethyl)-5-azanyl-6-oxidanyl-6-oxidanylidene-hexyl]-tris(oxidanyl)boron, ... (4 entities in total)
• 機能のキーワード: arginase, inhibitor, complex, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 110510.77

構造登録者

Petersen, J. (登録日: 2023-12-12, 公開日: 2024-11-27, 最終更新日: 2024-12-25)

主引用文献

Mlynarski, S.N.,Aquila, B.M.,Cantin, S.,Cook, S.,Doshi, A.,Finlay, M.R.V.,Gangl, E.T.,Grebe, T.,Gu, C.,Kawatkar, S.P.,Petersen, J.,Pop-Damkov, P.,Schuller, A.G.,Shao, W.,Shields, J.D.,Simpson, I.,Tavakoli, S.,Tentarelli, S.,Throner, S.,Wang, H.,Wang, J.,Wu, D.,Ye, Q.
Discovery of (2 R ,4 R )-4-(( S )-2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer.
J.Med.Chem., 67:20827-20841, 2024

PubMed Abstract: Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading to poor passive permeability and low oral exposure. Using structure-based drug design, we discovered a novel proline-based arginase inhibitor () that was potent but had low oral bioavailability in rat. This issue was addressed by incorporating amino acids to target PepT1/2 active transport, followed by in vivo hydrolysis post absorption. The hydrolysis rate was highly tunable, and the valine prodrug () showed the best balance of stability and exposure of the potent payload. Dosing of in mouse xenograft models significantly increased arginine in the tumor microenvironment, resulting in tumor growth inhibition as a monotherapy and in combination with an anti-PD-L1 antibody. Compound (AZD0011) displays good pharmacokinetics and was selected as a clinical drug candidate for cancer.

PubMed: 39572889
DOI: 10.1021/acs.jmedchem.4c02309

実験手法

X-RAY DIFFRACTION (1.76 Å)