Non-cytotoxic HDAC3-selective degraders built on a propyl hydrazide zinc-binder
- Class I HDAC degraders were designed from the HDAC3-preferring inhibitor FL-007, using a propyl hydrazide zinc-binding group and testing two linker exit vectors.
- The compounds inhibited HDAC1, HDAC2 and HDAC3 to varying degrees yet selectively depleted HDAC3, shown by immunoblotting and HiBiT/LgBiT assays across several cell lines.
- They were not cytotoxic in cancer or normal cells; HDAC3 loss gave a modest cisplatin-sensitizing effect in resistant cells, weaker than with cytotoxic inhibitors, tracking with higher histone H3 acetylation and p21.
💡 Points
Degradation decoupled from inhibition here: compounds still hit HDAC1/2 yet only HDAC3 disappears, so the linker exit vector, not the ZBG, is steering isoform selectivity. That's the useful lesson for ternary-complex design. But non-cytotoxic plus weak cisplatin sensitization suggests HDAC3 scaffolding loss alone is a soft phenotype. I'd want a catalytic-dead rescue before believing a degrader advantage.