Beyond CRBN and VHL: DCAF16-Recruiting Degraders from Rational Design to Clinical Translation

Abstract Targeted protein degradation (TPD) has revolutionized modern drug discovery. However, the current clinical landscape remains predominantly reliant on CRBN and VHL, restricting the targetable proteome and increasing the risk of acquired resistance. Expanding the TPD toolbox with therapeutically tractable E3 ligases is imperative. Recently, DCAF16 has emerged as a frontrunner in this effort, underscored by the advancement of DCAF16-based monovalent degraders such as PLX-61639 and AMX-883 toward clinical evaluation. Unlike the historically serendipitous discovery of CRBN-based molecular glues, DCAF16 offers a versatile platform for the rational design of both bifunctional and monovalent degraders. In this timely perspective, we present the first comprehensive medicinal chemistry analysis of the DCAF16-mediated degradation landscape, focusing on delineating the expanding diversity of recruiting motifs and elucidating the design principles, structural basis, and SAR of representative degraders. Finally, we outline current challenges and offer insights into future design strategies and clinical translation of DCAF16-based degraders.