A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity

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 CRL4CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4CRBN neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4CRBN molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.

 

Comments:

It sounds like your work is focused on addressing a critical challenge in the field of targeted protein degradation using PROTACs. Selectivity in these molecules is crucial for their effectiveness as pharmacological tools and clinical agents.

Your approach seems multi-faceted. Leveraging structural insights from known CRL4CRBN neo-substrates to modify Thalidomide derivatives used for PROTACs is a clever strategy. By attenuating the monovalent degradation function in well-known molecular glue degraders like CC-885 and Pomalidomide, you're aiming to enhance selectivity.

Moreover, applying these design principles to improve the selectivity profile of a previously published BRD9 PROTAC (dBRD9-A) showcases the versatility and applicability of your approach across different target proteins.

The incorporation of a computational modeling pipeline to assess the impact of your modifications on ternary complex formation is a forward-thinking step. This not only validates the effectiveness of your design in blocking degrons but also ensures that the modifications don't hinder the essential interaction required for protein degradation.

Overall, your work appears to offer valuable tools and principles that can significantly contribute to advancing the development of targeted protein degradation strategies. Selectivity enhancement is a critical step in optimizing the efficacy and safety of these pharmacological tools.

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S8300	CC-885	CC-885 is a novel cereblon (CRBN) modulator. CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation.

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