One molecule hits both HDAC and the proteasome, outperforming its parent in breast cancer models
- Starting from the earlier lead ZY-2, the foot pocket binder, linker and terminal aryl group were varied systematically to build a dual HDAC/proteasome series.
- Deprotecting hit X17 gave X26, which keeps strong proteasome inhibition and leans toward HDAC2 over HDAC1, with good selectivity against HDAC6 and HDAC8.
- X26 was far more potent than ZY-2 against cancer cells, notably triple-negative MDA-MB-231, suppressing colonies, triggering apoptosis and DAMP release linked to immunogenic cell death.
- In an MDA-MB-231 xenograft it beat ZY-2.
💡 Points Based on the abstract
Dual HDAC/proteasome pharmacology is hard to attribute: with one scaffold hitting both, the xenograft win over ZY-2 could come from either arm or from synergy. I'd want matched single-target controls and a bortezomib plus HDAC inhibitor combination as the benchmark. I'd also confirm the HDAC2 lean holds in cells, and check exposure, since a freshly unmasked polar group often hurts PK.