Paper: Unveiling Molecular Glue-like Degraders: CRISPR Screen Reveals Promising Pathway

Summary of research paper: CRISPR Screen Reveals BRD2/4 Molecular Glue-like Degrader via Recruitment of DCAF16

Study Authors: Andrea G. Shergalis, Violeta L. Marin, David Y. Rhee, Sameera Senaweera, Rebecca L. McCloud, Judith A. Ronau, Charles W. Hutchins, Shaun McLoughlin, Kevin R. Woller, Scott E. Warder, Anil Vasudevan, and Justin M. Reitsma.

Molecular glues (MGs) are a group of compounds that enhance protein interactions, offering potential in drug development. Recent studies highlighted MG effects in clinical drugs, like thalidomide and indisulam, by influencing interactions between proteins and specific ubiquitin ligases. However, discovering new MGs remains challenging. In this article, we explore a recent study that used CRISPR technology to uncover a promising MG degrader involving BRD2/4 and DCAF16.

Discovering the Essential Component:

Researchers conducted a CRISPR/Cas9 knock-out screen to identify proteins essential for degrading BRD4. Using compound 1a, a JQ1-based degrader, they identified DCAF16, a crucial component of the Cul4 ligase complex, as essential for the degrader’s effectiveness.

Compound 1a: Unlocking BRD2/4 and DCAF16 Interaction:

Compound 1a was found to act as a molecular glue degrader, promoting interaction between DCAF16 and BRD2/4. This interaction facilitated target protein degradation, unveiling new insights into MG mechanisms.

Prospects for Future MG Discovery:

These findings have implications for prospective MG discovery and our understanding of protein interactions. Expanding the repertoire of MGs could lead to innovative strategies for targeted protein degradation. The success of the CRISPR/Cas9 screen highlights its potential in unraveling complex protein networks and identifying MG candidates.

Conclusion:

The discovery of a molecular glue-like degrader involving BRD2/4 and DCAF16 showcases the potential of MGs in targeted protein degradation. The study’s findings shed light on MG mechanisms and pave the way for future MG discoveries and novel therapeutics. As researchers delve deeper into protein interactions, the possibilities for innovative drug development continue to expand.

Citation and References:

DOI: 10.1021/acschembio.2c00747