Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity

Here, we present
a new series of hydrazide-bearing class I selective
HDAC inhibitors designed based on panobinostat. The cap, linker, and
zinc-binding group were derivatized to improve HDAC affinity and antileukemia
efficacy. Lead inhibitor 13a shows picomolar or low nanomolar
IC50 values against HDAC1 and HDAC3 and exhibits differential
toxicity profiles toward multiple cancer cells with different FLT3
and p53 statuses. 13a indirectly inhibits the FLT3 signaling
pathway and down-regulates master antiapoptotic proteins, resulting
in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells.
While in the wt-FLT3 and p53-null cells, 13a is incapable
of causing apoptosis at a therapeutic concentration. The MDM2 antagonist
and the proteasome inhibitor promote 13a-triggered apoptosis
by preventing p53 degradation. Furthermore, we demonstrate that apoptosis
rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability
and a higher AUC0‑inf value.