High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery

被引：50

作者：

Craven, Gregory B. ^{[1
,2
]}

Affron, Dominic P. ^{[1
]}

Allen, Charlotte E. ^{[1
]}

Matthies, Stefan ^{[1
]}

Greener, Joe G. ^{[2
]}

Morgan, Rhodri M. L. ^{[2
]}

Tate, Edward W. ^{[1
]}

Armstrong, Alan ^{[1
]}

Mann, David J. ^{[2
]}

机构：

[1] Imperial Coll London, Dept Chem, South Kensington Campus, London SW7 2AZ, England

[2] Imperial Coll London, Dept Life Sci, South Kensington Campus, London SW7 2AZ, England

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2018年 / 57卷 / 19期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

Cdk2; covalent inhibition; fragment-based drug discovery; kinetics; protein modification; DRUG DISCOVERY; IRREVERSIBLE INHIBITORS; BINDING FRAGMENTS; PROTEIN-KINASES; CANCER-THERAPY; ASSAY; BIOLOGY; DESIGN; THIOLS; PROBES;

D O I：

10.1002/anie.201711825

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.

引用

页码：5257 / 5261

页数：5

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