Perspective surveys DCAF16 as an E3 ligase beyond CRBN and VHL, covering recruiting motifs, design principles and clinical outlook
- This perspective reviews the medicinal chemistry of degraders that recruit the E3 ligase DCAF16, motivated by the field's heavy reliance on CRBN and VHL.
- It catalogs the growing variety of DCAF16-recruiting motifs and discusses structural rationale and SAR of representative bifunctional and monovalent degraders, including clinical-stage examples PLX-61639 and AMX-883.
- It closes with remaining challenges and suggested design strategies for clinical translation.
💡 Points Based on the abstract
Does DCAF16 actually earn a place next to CRBN and VHL? Its draw is that monovalent, low-molecular-weight covalent handles can recruit it, sidestepping PROTAC size and permeability penalties. The catch is that many hits look cysteine-reactive, so I'd ask how much target scope is real versus ligand-specific, and whether proteome-wide selectivity holds.
Beyond CRBN and VHL: DCAF16-Recruiting Degraders from Rational Design to Clinical Translation ↗