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Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1

Accepted version
Peer-reviewed

Type

Article

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Authors

Lopes Bernardes, Goncalo  ORCID logo  https://orcid.org/0000-0001-6594-8917

Abstract

PROTAC 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.

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Journal Title

ChemBioChem: a European journal of chemical biology

Conference Name

Journal ISSN

1439-4227

Volume Title

Publisher

Wiley-VCH Verlag
Sponsorship
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (101022421)
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 101022421 (L.A.R.C.). D.Z. was supported by the Blavatnik Cambridge Fellowship, funded by the Blavatnik Family Foundation. This study was supported by Fundação para a Ciência e a Tecnologia (FCT, Portugal) through project SFRH/BD/143583/2019 (B.B.S).
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