Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia

Using
a microwave-assisted protocol, we synthesized 16
peptoid-capped
HDAC inhibitors (HDACi) with fluorinated linkers and identified two
hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic
potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low
cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase
inhibitor decitabine in AML cell lines. The comparison of crystal
structures of HDAC6 complexes with 10h and its nonfluorinated
counterpart revealed a similar occupation of the L1 loop pocket but
slight differences in zinc coordination. The substitution pattern
of the acyl residue turned out to be crucial in terms of isoform selectivity.
The introduction of an isopropyl group onto the phenyl ring provided
the highly HDAC6-selective inhibitor 10p, which demonstrated
moderate synergy with decitabine and exceeded the HDAC6 selectivity
of tubastatin A.