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  2. Identifying eleven new ferroptosis inhibitors as neuroprotective agents from FDA-approved drugs

Identifying eleven new ferroptosis inhibitors as neuroprotective agents from FDA-approved drugs

  • Bioorg Chem. 2024 Mar 5:146:107261. doi: 10.1016/j.bioorg.2024.107261.
Qingyun Tan 1 Deyin Wu 1 Yating Lin 1 Haopeng Ai 1 Jun Xu 1 Huihao Zhou 1 Qiong Gu 2
Affiliations

Affiliations

  • 1 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. Electronic address: guqiong@mail.sysu.edu.cn.
Abstract

With increasing evidence that Ferroptosis is associated with diverse neurological disorders, targeting Ferroptosis offers a promising avenue for developing effective pharmaceutical agents for neuroprotection. In this study, we identified Ferroptosis inhibitors as neuroprotective agents from US Food and Drug Administration (FDA)-approved drugs. 1176 drugs have been screened against erastin-induced Ferroptosis in HT22 cells, resulting in 89 Ferroptosis inhibitors. Among them, 26 drugs showed significant activity with EC50 below10 μM. The most active Ferroptosis inhibitor is lumateperone tosylate at nanomolar level. 11 drugs as Ferroptosis inhibitors were not reported previously. Further mechanistic studies revealed that their mechanisms of actions involve free radical scavenging, Fe2+ chelation, and 15-lipoxygenase inhibition. Notably, the active properties of some drugs were firstly revealed here. These Ferroptosis inhibitors increase the chemical diversity of Ferroptosis inhibitors, and offer new therapeutic possibilities for the treatments of related neurological diseases.

Keywords

15-Lipoxygenase inhibitor; FDA-approved drugs; Fe(2+) chelator; Ferroptosis inhibitor; Free radical scavenger; Neuroprotection.

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