Replacing a Cereblon Ligand by a DDB1 and CUL4 Associated Factor 11 (DCAF11) Recruiter Converts a Selective Histone Deacetylase 6 PROTAC into a Pan‐Degrader

Abstract Proteolysis‐targeting chimeras (PROTACs) have recently gained popularity as targeted protein degradation (TPD) promises to overcome the limitations of occupancy‐driven pharmacology. However, most degraders rely on a small number of E3 ligases. In this study, we present the first‐in‐class histone deacetylase (HDAC) PROTACs recruiting the DDB1‐ and CUL4‐ associated factor 11 (DCAF11). We established a synthesis route entirely on solid‐phase to prepare a set of eleven degraders. The long and flexible spacer bearing FF2039 ( 1j ) showed significant HDAC1 and 6 degradation in combination with cytotoxicity against the multiple myeloma cell line MM.1S. Further investigations revealed that 1j was also able to degrade HDAC isoforms of class I, IIa and IIb. Compared to our previously published cereblon‐recruiting HDAC6 selective PROTAC A6 , we succesfully transformed the selective degrader into a pan‐HDAC degrader by switching the recruited E3 ligase. A detailed profiling of the anticancer properties of 1j demonstrated its significant antiproliferative activity against both hematological and solid cancer cell lines, driven by cell cycle arrest and apoptosis induction.