An engineered cereblon optimized for high throughput screening and molecular glue discovery

Bailey et al., An engineered cereblon optimized for high throughput screening and molecular glue discovery, Cell Chemical Biology (2024).        

Credits for Summary: Khyati Shukla Aakash Khurana

The research focuses on the development and characterization of CRBN (Cereblon)-based molecular glues and PROTACs (Proteolysis Targeting Chimeras) to enhance targeted protein degradation. The authors engineered a simplified CRBN construct, termed CRBN_DHBD, to facilitate high-throughput screening and chemo-proteomics approaches. This construct aimed to overcome previous limitations in studying CRBN interactions, allowing for a more efficient identification of potential molecular glue substrates.

To identify effective CRBN binders, the researchers created the "Enamine CRBN focused IMiD library," which consisted of 4480 IMiD derivatives. High-throughput screening was conducted using various assays, including fluorescence polarization and mass spectrometry, to evaluate binding interactions and ternary complex formation with target proteins. The results demonstrated that the CRBN_DHBD construct exhibited improved binding affinity and specificity, successfully forming ternary complexes with PROTACs and leading to effective degradation of specific proteins such as IKZF1, GSPT1, and SALL4 in cellular assays.

The findings underscore the potential of CRBN-based molecular glues and PROTACs in therapeutic applications, highlighting the importance of optimizing protein constructs and employing high-throughput methods for drug discovery. The successful identification of high-potency binders paves the way for the development of next-generation CRBN glues, which could significantly impact targeted protein degradation therapies. Overall, this research provides valuable insights into CRBN interactions and establishes a foundation for future studies aimed at harnessing the therapeutic potential of molecular glues and PROTACs.