4.8 Article

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

期刊

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 57, 期 19, 页码 5257-5261

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201711825

关键词

Cdk2; covalent inhibition; fragment-based drug discovery; kinetics; protein modification

资金

  1. Institute of Chemical Biology (Imperial College London)
  2. UK Engineering and Physical Sciences Research Council [EP/F500416/1]
  3. Biotechnology and Biological Sciences Research Council [BB/J014575/1]
  4. Cancer and Polio Research Fund

向作者/读者索取更多资源

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.

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