Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The RAS-RAF-MEK-ERK signaling pathway drives cancer cell growth and malignancy.
• Drug resistance to RAF or MEK inhibitors is a significant clinical challenge, often involving ERK reactivation.
• ERK remains a critical target for developing new anti-cancer therapies.

Purpose of the Study:

• To design and characterize novel bivalent inhibitors targeting the Extracellular signal-Regulated Kinase (ERK).
• To investigate the potential of combining ATP-binding pocket inhibitors with peptides targeting the D-site recruitment site (DRS).
• To evaluate the potency and specificity of these novel bivalent inhibitors.

Main Methods:

• Design of bivalent inhibitors using click chemistry, linking small molecule ATP-binding inhibitors with ERK-targeting peptides.
• Structural and functional characterization of bivalent inhibitors, including potency and specificity assays.
• Assessment of inhibitor binding to ERK and related kinases, including those with a DRS.

Main Results:

• The lead bivalent inhibitor, SBP3, demonstrated significantly improved potency compared to the small molecule inhibitor alone.
• SBP3 exhibited binding to several ERK-related kinases possessing a DRS, underscoring the need for specificity verification.
• SBP3 did not inhibit other kinases within the CMGC branch, indicating some selectivity.

Conclusions:

• Bivalent inhibitors combining ATP-site and DRS-targeting elements represent a promising strategy for overcoming ERK-mediated drug resistance.
• The modular design allows for versatile combinations of inhibitors and peptides for tailored therapeutic approaches.
• Experimental validation of specificity is crucial for bivalent inhibitor development due to potential off-target interactions with related kinases.