2. Academic Validation
  3. Discovery of DCAF16 Binders for Targeted Protein Degradation

Discovery of DCAF16 Binders for Targeted Protein Degradation

  • ACS Chem Biol. 2025 Feb 21;20(2):479-488. doi: 10.1021/acschembio.4c00799.
Miguel A Campos 1 2,  Isabella A Riha 1,  Chenlu Zhang 1,  Chen Mozes 1,  Karl A Scheidt 1 2 3,  Xiaoyu Zhang 1 2 4 5 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
  • 2 Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States.
  • 3 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 4 International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.
  • 5 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 6 Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
PMID: 39882752 DOI: 10.1021/acschembio.4c00799
Abstract

Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted protein degradation (TPD) offers an alternative approach by harnessing cellular degradation pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD by identifying additional E3 Ligases, with DCAF16 emerging as a promising candidate for facilitating protein degradation through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms. In this study, we revisited a previously reported compound and discovered that it covalently binds to DCAF16. We further optimized it into a FKBP12-targeting PROTAC, MC-25B. This PROTAC engages DCAF16 at cysteines C177-179, leading to the degradation of nuclear-localized FKBP12. We further demonstrated the versatility of this DCAF16 recruiter by degrading additional endogenous proteins. Compared to the first-generation DCAF16-based PROTAC, which was derived from a fragment electrophile, this DCAF16 recruiter-based PROTAC exhibits improved proteome-wide selectivity.

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