Discovery of Potent and Non-cytotoxic HDAC3-Selective Degraders Featuring a Propyl Hydrazide Zinc-Binding Group

Histone deacetylase 3 (HDAC3) is an important therapeutic target in cancer, yet selective HDAC3 degraders remain limited. In this study, we report the development of novel class I HDAC degraders derived from the HDAC3-preferential inhibitor FL-007. Two linker exit vectors were investigated, leading to the identification of a series of potent compounds (2a−d) exhibiting low micromolar inhibition of HDAC2 and submicromolar inhibition of HDAC1 and HDAC3, together with selective HDAC3 degradation. Degradation activity was confirmed in MM.1S, HCT116, A2780-HDAC3-HiBiT, and Cal27CisR cells using immunoblotting and HiBiT/LgBiT assays, achieving Dmax values of up to 92%. Notably, these compounds showed no cytotoxicity up to 100 μM in both cancerous and non-cancerous cell lines. Selective HDAC3 degradation resulted in moderate chemosensitization of cisplatin-resistant Cal27CisR cells, in contrast to the stronger effects observed with cytotoxic HDAC inhibitors. For compound 2b, the chemosensitizing effect was associated with increased histone H3 acetylation and increased p21 expression.