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.