Acetyl-CoA Carboxylase Proteolysis-Targeting Chimeras: Conceptual Design and Application as Insecticides

Novel approaches for pest control are essential to ensure a sufficient food supply for the growing global population. The development of new insecticides must meet rigorous regulatory requirements for safety and address the resistance issues of existing insecticides. Proteolysis-targeting chimeras (PROTACs), originally developed for human diseases, show promise in agriculture. They offer innovative insecticides tailored to overcome resistance, opening avenues for agricultural applications. In this study, we developed small-molecule degraders by incorporating pomalidomide as an E3 ligand. These degraders were linked to a ligand (spirotetratmat enol) targeting the ACC protein through a flexible chain, aiming to achieve the efficient control of insects. Compounds <b>9a</b>-<b>9d</b> were designed, synthesized, and evaluated for biological activities and mechanisms. Among them, <b>9b</b> exhibited superior potency against <i>Aphis craccivora</i> (LC₅₀ = 107.8 μg mL^-1) compared to others and effectively degraded ACC proteins through the ubiquitin-proteasome system. These findings highlight the potential of utilizing PROTAC-based approaches in the development of insecticides for efficient pest control.