A dual HDAC3 and HDAC8 degrader for breast cancer

A proteolytic targeting chimera (PROTAC) that degrades the class I histone acetylation regulators HDAC3 and HDAC8 simultaneously could help treat breast cancers by inhibiting cell cycle progression and inducing apoptosis.

Structure-guided optimization resulted in a piperazine-based warhead that was coupled to an alkane linker and a vHL recruiting ligand, yielding a compound that selectively degraded HDAC3 and HDAC8 with EC50s of 1.7 nM and 6.1 nM, respectively, in human breast cancer cell lines. In the same cells, the compound did not affect the other class I HDACs, HDAC1 and HDAC2, nor did it significantly alter gene expression. ...