Category: Assay Development and Screening

1318-D - High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery

Tuesday, February 6, 2018
5:00 PM - 6:00 PM

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. A high-throughput assay is described that facilitates robust kinetic analysis of electrophile-thiol conjugation, effective for both small molecule- and protein-derived thiols in combination with any irreversibly thiol-reactive ligand. Crucial to its success is its ability to account for variations in intrinsic reactivity observed within electrophilic fragment libraries by comparing reactivity between target- and control-thiols. The method is applied prospectively to discover covalent fragments that target a clinically important kinase. Crystal structures of the inhibitor complexes validate the approach and guide further optimisation. The power of this technique is highlighted by the identification of kinase-selective probes whose novel mode-of-action may offer future therapeutic potential.

Gregory Craven

Imperial College London
London, England, United Kingdom

Greg is a post-doctoral research associate at Imperial College London working in the fields of chemical biology and drug discovery.