BENZIMIDAZOLE SCAFFOLDS IN PROTAC DESIGN: BRIDGING E3 LIGASE RECRUITMENT AND TARGETED PROTEIN DEGRADATION A REVIEW

Mahesh Kumar N.*, Priya and Dr. Shachindra L. Nargund

ABSTRACT

Benzimidazole scaffolds have gained renewed attention in the field of targeted protein degradation, particularly
within the design of proteolysis targeting chimeras (PROTACs). These heterobifunctional molecules operate by
simultaneously engaging a protein of interest and an E3 ubiquitin ligase, ultimately leading to selective
proteasomal degradation of the target pr otein. The structural features of benzimidazoles, including their planar
heteroaromatic core, hydrogen bonding potential, and synthetic flexibility, make them attractive for incorporation
into both warhead and E3 ligase ligand domains of PROTACs. Recent ad vances have demonstrated that
benzimidazole based cereblon ligands can serve as alternatives to classical immunomodulatory imide drugs,
offering opportunities to modulate binding profiles and reduce off target degradation. Moreover, benzimidazole
containin g inhibitors of kinases, bromodomains, and other therapeutic targets have been successfully adapted into
PROTAC architectures. This review highlights current design strategies, structure activity relationships, and
emerging trends, underscoring the potenti al of benzimidazoles to expand the chemical diversity and therapeutic
scope of PROTAC technology.

Keywords: Benzimidazole, Chemical diversity, E3 ligase, Heterobifunctional, PROTACs.