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

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 (-) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. In contrast, the phenyl glutarimide-based series (-) displayed low cytotoxicity, no neosubstrate degradation, and enhanced chemical stability. The hit compounds from both series, (DC = 20 nM, = 99%) and (DC = 81 nM, = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with 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.