Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor crucial for RAS protein activation.
• Aberrant RAS signaling, modulated by SOS1, is implicated in approximately 30% of human cancers, making SOS1 a significant therapeutic target.
• Developing small molecules to modulate SOS1 activity is a key strategy in cancer therapy.

Purpose of the Study:

• To discover and characterize a new series of benzimidazole-derived SOS1 agonists.
• To evaluate the potency and mechanism of action of these novel compounds.
• To establish these compounds as potential therapeutic agents for RAS-driven cancers.

Main Methods:

• Structure-guided drug design was employed to synthesize benzimidazole derivatives.
• In vitro assays were used to measure nucleotide exchange on RAS and binding affinity to SOS1.
• Cellular assays assessed the impact on RAS-GTP levels and ERK1/2 phosphorylation.
• Structure-activity relationships were analyzed.

Main Results:

• A novel series of benzimidazole-derived SOS1 agonists was identified.
• These compounds demonstrated submicromolar potency for increasing RAS nucleotide exchange in vitro.
• Low double-digit nanomolar affinity for SOS1 binding was achieved.
• Rapid enhancement of cellular RAS-GTP levels and biphasic ERK1/2 phosphorylation were observed.
• The developed compounds represent the most potent SOS1 agonists reported to date.

Conclusions:

• The newly synthesized benzimidazole derivatives are potent SOS1 agonists.
• These compounds effectively modulate RAS signaling pathways in vitro and in cells.
• This series of compounds holds significant promise as a therapeutic strategy for cancers associated with aberrant RAS activation.