Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• The RAS/RAF/MEK/ERK pathway is a key target in oncology drug development.
• Acquired resistance to B-RAF and MEK inhibitors can still allow for ERK1/2 inhibition.
• Existing ERK1/2 inhibitors include noncovalent and promiscuous covalent types.

Purpose of the Study:

• To identify novel, highly selective covalent ERK1/2 inhibitors.
• To explore structure-based drug design (SBDD) for covalent inhibitor development.
• To generate tool compounds for evaluating covalent ERK1/2 inhibition strategies.

Main Methods:

• Structure-based drug design (SBDD) was employed.
• Exploited existing ERK1/2 inhibitors and high-throughput screening (HTS) hits.
• Synthesized and characterized multiple series of covalent inhibitors.

Main Results:

• Identification of multiple series of highly selective covalent ERK1/2 inhibitors.
• Compounds were informed by SBDD principles.
• Selective covalent tool compounds were generated.

Conclusions:

• Novel covalent ERK1/2 inhibitors have been identified.
• These compounds can serve as tools for further research.
• The potential benefits of targeting the pathway via covalent ERK1/2 inhibition warrant investigation.