Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders

Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode of action. In this work, we report the design, synthesis, and biological evaluation of the first-in-class selective degraders of the class IIb histone deacetylases (HDACs) 6 and 10. To this end, the dual HDAC6/10 inhibitor tubastatin A and a ring-opened analog were connected via well-established PROTAC linkers to pomalidomide and phenylglutarimides as cereblon recruiters. This approach led to the discovery of AP1 (HDAC6 DC₅₀ = 13 nM; HDAC10 DC₅₀ = 29 nM) as a potent degrader of class IIb HDACs. Importantly, AP1 neither degraded HDAC1/8 (class I) and HDAC4/7 (class IIa), nor induced histone H3 hyperacetylation, thereby confirming its selectivity for class IIb HDACs. Due to its low cytotoxicity against hematological and solid cancer cell lines, AP1 represents a valuable tool compound for the chemical knockdown of class IIb HDACs.