First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

HDAC
inhibitors are an attractive class of cytotoxic agents for
the design of hybrid molecules. Several HDAC hybrids have emerged
over the years, but none combines HDAC inhibition with ferroptosis,
a combination which is being extensively studied because it leads
to enhanced cytotoxicity and attenuated neuronal toxicity. We combined
the pharmacophores of SAHA and CETZOLE molecules
to design the first-in-class dual mechanism hybrid molecules, which
induce ferroptosis and inhibit HDAC proteins. The involvement of both
mechanisms in cytotoxicity was confirmed by a series of biological
assays. The cytotoxic effects were evaluated in a series of cancer
and neuronal cell lines. Analogue HY-1 demonstrated the
best cytotoxic profile with GI50 values as low as 20 nM.
Although the increase in activity of the hybrids over the combinations
is modest in cellular systems, they have the potential advantage of
homogeneous spatiotemporal distribution in in vivo systems.