Article ; Online: Advances in covalent drug discovery.
Nature reviews. Drug discovery
2022 Volume 21, Issue 12, Page(s) 881–898
Abstract: Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable ... ...
| Abstract | Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through 'electrophile-first' approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field. |
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| MeSH term(s) | Humans ; Drug Discovery/methods ; Ligands ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins p21(ras)/metabolism ; SARS-CoV-2 ; Structure-Activity Relationship ; COVID-19 Drug Treatment |
| Chemical Substances | Ligands ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; BTK protein, human (EC 2.7.10.2) ; EGFR protein, human (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2022-08-25 |
| Publishing country | England |
| Document type | Journal Article ; Review |
| ZDB-ID | 2062954-0 |
| ISSN | 1474-1784 ; 1474-1776 |
| ISSN (online) | 1474-1784 |
| ISSN | 1474-1776 |
| DOI | 10.1038/s41573-022-00542-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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