Discovery of histone deacetylase 8 (HDAC8)-specific proteolysis-targeting chimeras with anti-cancer activity against hematological malignancies

Histone deacetylase 8 (HDAC8) has emerged as a promising therapeutic target for several malignancies. In this study, we developed two series of cereblon (CRBN)-recruiting proteolysis-targeting chimeras (PROTACs) for targeted HDAC8 degradation, utilizing the selective HDAC8 inhibitor PCI-34051 as warhead. The pomalidomide/thalidomide-based series (BP1–BP5) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. In contrast, the phenyl glutarimide (PG)-based series (BP6–BP10) displayed low cytotoxicity, no neosubstrate degradation, and enhanced chemical stability. The hit compounds from both series, BP1 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%) and its PG-based counterpart BP6 (DC50, 24 h = 81 nM, Dmax, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. A high-throughput drug synergy screen revealed that BP6-treated HL60 leukemia cells exhibited significantly enhanced sensitivity to the MEK inhibitor cobimetinib, suggesting that HDAC8 degradation may potentiate the therapeutic efficacy of MEK inhibition.