Potent Hydrazide-Based HDAC Inhibitors with a Superior Pharmacokinetic Profile for Efficient Treatment of Acute Myeloid Leukemia In Vivo

As
“Michael acceptors” may induce promiscuous responses
in mammalian cells by reacting with various proteins, we modified
the cinnamamide of our previous hydrazide-based HDAC inhibitors (HDACIs)
to deactivate the Michael reaction. Representative compound 11h is 2–5 times more potent than lead compound 17 in both HDAC inhibitory activity (IC50 = 0.43–3.01
nM) and cell-based antitumor assay (IC50 = 19.23–61.04
nM). The breakthrough in the pharmacokinetic profile of 11h (oral bioavailability: 112%) makes it a lead-in-class oral active
agent, validated in the in vivo anti-AML study (4
mg/kg p.o., TGI = 78.9%). Accumulated AcHH3 and AcHH4 levels in tumor
tissue directly correlate with the in vivo efficacy,
as panobinostat with lower AcHH3 and AcHH4 levels than 11h displays limited activity. To the best of our knowledge, this work
contributes the first report of in vivo antitumor
activity of hydrazide-based HDACIs. The outstanding pharmacokinetic/pharmacodynamic
and antitumor activity of 11h could potentially extend
the clinical application of current HDACIs.