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 (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 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%)
and BP6 (DC50, 24 h = 81 nM, Dmax, 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.