HDAC/proteasome dual inhibitor X26 improves on its parent in solid-tumor models
- Starting from the earlier lead ZY-2, the team varied the foot-pocket group, linker and terminal aryl to build new HDAC/proteasome dual inhibitors.
- X17 emerged as the potent dual hit, and deprotecting it gave X26, which keeps strong proteasome inhibition and prefers HDAC2 over HDAC1 while sparing HDAC6 and HDAC8.
- X26 was much more antiproliferative than ZY-2, notably in triple-negative MDA-MB-231 cells, with antitumor activity in solid tumor models.
💡 Points Based on the abstract
Class I HDAC selectivity inside a single molecule is rare, and HDAC2 over HDAC1 is a real differentiator. Dual-target molecules have a balance problem, though: proteasome potency far above HDAC potency makes it effectively a proteasome inhibitor with a liability. I'd want matched single-target controls to show the combination is what drives cell killing.
📄 Paper · European Journal of Medicinal Chemistry (Elsevier) ↗ Discovery and optimization of novel HDAC/proteasome dual inhibitors with antitumor activity in solid tumor models