6QEF

CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR (S)-3-Hydroxy-2-oxo-1-phenyl-pyrrolidine-3-carboxylic acid 3-chloro-5-fluoro-benzylamide

6QEF の概要

• エントリーDOI: 10.2210/pdb6qef/pdb
• 分子名称: Methionine aminopeptidase 2, 1,2-ETHANEDIOL, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: hydrolase, peptidase, metal ion binding, proteolysis, hydrolase-hydrolase inhibitor complex
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43345.30

構造登録者

Musil, D.,Heinrich, T.,Lehmann, M. (登録日: 2019-01-07, 公開日: 2019-05-01, 最終更新日: 2024-05-15)

主引用文献

Heinrich, T.,Seenisamy, J.,Blume, B.,Bomke, J.,Calderini, M.,Eckert, U.,Friese-Hamim, M.,Kohl, R.,Lehmann, M.,Leuthner, B.,Musil, D.,Rohdich, F.,Zenke, F.T.
Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors.
J.Med.Chem., 62:5025-5039, 2019

PubMed Abstract: Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC of 1.9 μM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.

PubMed: 30939017
DOI: 10.1021/acs.jmedchem.9b00041

実験手法

X-RAY DIFFRACTION (1.79 Å)