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

Abstract

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 <b>11h</b> is 2-5 times more potent than lead compound <b>17</b> 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 <b>11h</b> (oral bioavailability: 112%) makes it a lead-in-class oral active agent, validated in the <i>in vivo</i> anti-AML study (4 mg/kg p.o., TGI = 78.9%). Accumulated AcHH3 and AcHH4 levels in tumor tissue directly correlate with the <i>in vivo</i> efficacy, as panobinostat with lower AcHH3 and AcHH4 levels than <b>11h</b> displays limited activity. To the best of our knowledge, this work contributes the first report of <i>in vivo</i> antitumor activity of hydrazide-based HDACIs. The outstanding pharmacokinetic/pharmacodynamic and antitumor activity of <b>11h</b> could potentially extend the clinical application of current HDACIs.