Discovery of DCAF16 Binders for Targeted Protein Degradation

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.