Selective HDAC11 inhibitor PB151 curbs liver cancer by rewiring lipid metabolism
- Structure-guided design yielded PB151, a potent HDAC11 inhibitor with strong selectivity against other HDAC isoforms.
- In liver cancer cells it engages HDAC11, raises levels of the substrate SHMT2, slows proliferation and triggers apoptosis.
- In an orthotopic mouse model, injected PB151 shrank tumor burden, extended survival and spared liver architecture without overt toxicity.
- Mechanistically it activates LKB1-AMPK signaling, lowers FASN and raises ACC1 phosphorylation, limiting lipid accumulation.
💡 Points
HDAC11 is the one isoform where selectivity is cheap to claim and hard to earn, since its fatty-acyl deacylase pocket differs from classic zinc-hydrolase HDACs. If PB151 really clears the other isoforms, that beats most hydroxamate-type tool compounds. But SHMT2 rising is the only engagement readout, and the LKB1-AMPK story looks downstream and possibly off-target. I'd want a cellular thermal shift and an inactive analog first; parenteral dosing also says little about oral exposure.