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 did neither degrade HDAC1/8 (class I) and HDAC4 (class IIa), nor did it induce 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.