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

ABSTRACT: 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.

SUBMITTER: Karaj E 

PROVIDER: S-EPMC10257520 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature