Abstract
Targeted covalent inhibitors have regained widespread attention in drug discovery and have emerged as powerful tools for basic biomedical research. Fueled by considerable improvements in mass spectrometry sensitivity and sample processing, chemoproteomic strategies have revealed thousands of proteins that can be covalently modified by reactive small molecules. Fragment-based drug discovery, which has traditionally been used in a target-centric fashion, is now being deployed on a proteome-wide scale thereby expanding its utility to both the discovery of novel covalent ligands and their cognate protein targets. This powerful approach is allowing ‘high-throughput’ serendipitous discovery of cryptic pockets leading to the identification of pharmacological modulators of proteins previously viewed as “undruggable”. The reactive fragment toolkit has been enabled by recent advances in the development of new chemistries that target residues other than cysteine including lysine and tyrosine. Here, we review the emerging area of covalent fragment-based ligand discovery, which integrates the benefits of covalent targeting and fragment-based medicinal chemistry. We discuss how the two strategies synergize to facilitate the efficient discovery of new pharmacological modulators of established and new therapeutic target proteins.
Highlights
Targeted covalent inhibitors have regained widespread attention in drug discovery and have emerged as powerful tools for basic biomedical research
Often serendipitous based on natural products such as the betalactam class of antibiotics exemplified by the discovery of penicillin or based on rational structure-based design from non-covalent inhibitors as exemplified by the development of covalent kinase inhibitors targeting EGFR or BTK
There has been a resurgence of interest in covalent inhibitors that has resulted in a host of new approaches for discovering and developing covalent inhibitors, resulting in 7 covalent drugs approved by the FDA from 2015 to 2019.9
Summary
Targeted covalent inhibitors have regained widespread attention in drug discovery and have emerged as powerful tools for basic biomedical research. Fragment-based drug discovery, which has traditionally been used in a target-centric fashion, is being deployed on a proteome-wide scale thereby expanding its utility to both the discovery of novel covalent ligands and their cognate protein targets. This powerful approach is allowing ‘high-throughput’ serendipitous discovery of cryptic pockets leading to the identification of pharmacological modulators of proteins previously viewed as ‘‘undruggable’’. We discuss how the two strategies synergize to facilitate the efficient discovery of new pharmacological modulators of established and new therapeutic target proteins
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