Advances in covalent drug discovery.
Nat Rev Drug Discov
; 21(12): 881-898, 2022 12.
Article
in English
| MEDLINE | ID: covidwho-2008295
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protein Kinase Inhibitors
/
COVID-19 Drug Treatment
Type of study:
Experimental Studies
/
Prognostic study
/
Randomized controlled trials
Limits:
Humans
Language:
English
Journal:
Nat Rev Drug Discov
Journal subject:
Pharmacology
/
Drug Therapy
Year:
2022
Document Type:
Article
Affiliation country:
S41573-022-00542-z
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