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

<jats:p> 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 <jats:bold>FL-007</jats:bold> . Two linker exit vectors were investigated, leading to the identification of a series of potent compounds ( <jats:bold>2a-d</jats:bold> ) 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 <jats:bold>2b</jats:bold> , the chemosensitizing effect was associated with increased histone H3 acetylation and increased p21 expression. </jats:p>