{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Karaj E"],"funding":["National Institute of Neurological Disorders and Stroke","National Cancer Institute","NINDS NIH HHS","NCI NIH HHS","National Institute of General Medical Sciences","NIGMS NIH HHS"],"pagination":["14764-14791"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10257520"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["65(21)"],"pubmed_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 <b>SAHA</b> and <b>CETZOLE</b> 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 <b>HY-1</b> demonstrated the best cytotoxic profile with GI<sub>50</sub> 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 <i>in vivo</i> systems."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids."],"pmcid":["PMC10257520"],"funding_grant_id":["R15 CA213185","R01NS112642","R35 GM131821","R15CA213185","R15GM120712","GM131821","R01 NS112642","R15 GM141712","R15 GM120712"],"pubmed_authors":["James AW","Karaj E","Kuganesan N","Knoff JR","Pflum MK","Koranne RA","Fu Y","Tillekeratne LMV","Taylor WR","Sindi SH","Kotsull LN","Shah Z"],"additional_accession":[]},"is_claimable":false,"name":"First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids.","description":"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 <b>SAHA</b> and <b>CETZOLE</b> 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 <b>HY-1</b> demonstrated the best cytotoxic profile with GI<sub>50</sub> 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 <i>in vivo</i> systems.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Nov","modification":"2026-05-29T01:52:49.726Z","creation":"2025-04-06T08:03:03.9Z"},"accession":"S-EPMC10257520","cross_references":{"pubmed":["36306372"],"doi":["10.1021/acs.jmedchem.2c01276"]}}