7OVL

Protein kinase MKK7 in complex with methoxycyclohexyl-substituted indazole

7OVL の概要

• エントリーDOI: 10.2210/pdb7ovl/pdb
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 7, 3-(2~{H}-indazol-3-yl)-~{N}-[[1-[(1~{R},2~{R})-2-methoxycyclohexyl]-1,2,3-triazol-4-yl]methyl]-5-(propanoylamino)benzamide (3 entities in total)
• 機能のキーワード: inhibitor, complex, mkk7, kinase, triazole, click-chemistry, cuacc, transferase
• 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: 36648.44

構造登録者

Buehrmann, M.,Wiese, J.N.,Mueller, M.P.,Rauh, D. (登録日: 2021-06-15, 公開日: 2022-07-20, 最終更新日: 2024-11-13)

主引用文献

Gehrtz, P.,Marom, S.,Buhrmann, M.,Hardick, J.,Kleinbolting, S.,Shraga, A.,Dubiella, C.,Gabizon, R.,Wiese, J.N.,Muller, M.P.,Cohen, G.,Babaev, I.,Shurrush, K.,Avram, L.,Resnick, E.,Barr, H.,Rauh, D.,London, N.
Optimization of Covalent MKK7 Inhibitors via Crude Nanomole-Scale Libraries.
J.Med.Chem., 65:10341-10356, 2022

PubMed Abstract: High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated conventional biological and biochemical methods such as western blots and liquid chromatography-mass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter.

PubMed: 35912476
DOI: 10.1021/acs.jmedchem.1c02206

実験手法

X-RAY DIFFRACTION (2.9 Å)