Proteomics

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A degron blocking strategy towards improved CRBN recruiting PROTAC selectivity

ABSTRACT: The different layers of complexity in PROTAC design have slowed the broad implementation of this novel pharmacological approach. Given the challenges and opportunities of CRL4CRBN hijacking PROTACs we set out to identify and develop broadly implementable strategies to generate PROTACs with improved specificity for their targets. We used structural analysis of known neo-substrate degrons to generate “degron blocked IMiD” analogues and validated that they did not degrade any known neo-substrates using quantitative proteomics. We then applied this strategy to a known BRD9 PROTAC (dBRD9-A) to generate a degron-blocking analogue with a specific degradation profile.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Fernando J. Sialana  

LAB HEAD: Jyoti S. Choudhary

PROVIDER: PXD038298 | Pride | 2023-07-10

REPOSITORIES: Pride

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Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4<sup>CRBN</sup> recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4<sup>CRBN</sup> recruiting PROTACs have well described  ...[more]

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