Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1

Chembiochem. 2024 Jan 9:e202300736. doi: 10.1002/cbic.202300736. Online ahead of print.ABSTRACTPROTAC linker design remains mostly an empirical task. We employed the PRosettaC computational software in the design of sulfonyl-fluoride-based PROTACs targeting acyl protein thioesterase 1 (APT1). The software efficiently generated ternary complex models from empirically-designed PROTACs and suggested alkyl linkers to be the preferred type of linker to target APT1. Western blotting analysis revealed efficient degradation of APT1 and activity-based protein profiling showed remarkable selectivity of an alkyl linker-based PROTAC amongst serine hydrolases. Collectively, our data suggests that combining PRosettaC and chemoproteomics can effectively assist in triaging PROTACs for synthesis and providing early data on their potency and selectivity.PMID:38195841 | DOI:10.1002/cbic.202300736

Source: Chembiochem - January 10, 2024 Category: Biochemistry Authors: Lu ís A R Carvalho B árbara B Sousa Daniel Zaidman Hannah Kiely-Collins Gon çalo J L Bernardes Source Type: research