Silicon-containing tubastatin A analogs yield selective HDAC3 inhibitor for liver fibrosis
- Tubastatin A was redesigned by changing both the cap group and the zinc-binding motif, introducing silicon-containing alkyl hydrazides to steer selectivity toward HDAC3.
- Lead compound 6b inhibited HDAC3 at low-nanomolar potency with clear selectivity over HDAC5, HDAC6 and HDAC8, and docking supported the binding mode. It showed antifibrotic effects in TGF-β-stimulated stellate and sinusoidal endothelial cell models, with favorable ADMET properties.
- In a CCl4 mouse liver fibrosis model, 6b lowered liver enzymes and fibrosis markers and improved histology, outperforming tubastatin A and nintedanib; it appeared to act by dampening TGF-β/Smad signaling via altered histone acetylation.
💡 Points
Changing both cap and zinc binder on an HDAC6-leaning scaffold and ending up HDAC3-selective is a clever pivot, and a silicon alkyl hydrazide is a chemotype I would happily add to my own collection. Still, I doubt docking alone proves the selectivity, and hydrazides raise metabolic and safety questions under chronic dosing. Beating nintedanib in a single CCl4 model encourages without settling anything.