Advances in covalent drug discovery

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Covalent drugs have a long history in treating diseases.
• Recent advancements in rational design tools have improved covalent drug development.
• Covalent inhibitors targeting EGFR and BTK are established cancer therapies.

Purpose of the Study:

• To review milestones in covalent drug discovery.
• To highlight lessons learned from covalent drug programs.
• To demonstrate how evolving techniques facilitate covalent drug success.

Main Methods:

• Addition of reactive functional groups to existing ligands.
• 'Electrophile-first' approaches for covalent ligand identification.
• Covalent screening technologies and chemoproteomics platforms.

Main Results:

• Discovery of covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease.
• Validation of covalent screening technologies for drug discovery.
• Chemoproteomics aids in ligand discovery, selectivity profiling, and target identification.

Conclusions:

• Covalent drug discovery has evolved significantly with new tools and techniques.
• Rational design and advanced screening methods are key to developing potent and selective covalent inhibitors.
• The field continues to advance, offering new therapeutic opportunities.