Discovery of Histone Deacetylase 8-Specific Proteolysis-Targeting Chimeras with Anticancer Activity against...

Histone deacetylase 8 (HDAC8) has emerged as 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-based series (BP6-BP10) displayed low cytotoxicity, no neosubstrate degradation, and enhanced chemical stability. The hit compounds from both series, BP1 (DC_50, 24 h = 20 nM, D_max, 24 h = 99%) and BP6 (DC_50, 24 h = 81 nM, D_max, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with BP6 enhanced the tumor suppressor p53 stability, thereby significantly increasing the sensitivity of leukemia cells to the MDM2 antagonist idasanutlin than PCI-34051, highlighting its unique potential for combinatorial therapy without impacting neosubstrates.