Abstract：
Ferroptosis, first coined in 2012, is an iron-dependent regulated cell death (RCD) characterized by the accumulation of lipid peroxides to toxic levels. This mechanism is currently being evaluated as a target for a variety of diseases offering new opportunities for drug design and development. Recent reports uncovered acyl-CoA synthetase long-chain 4 (ACSL4) as a critical contributor to ferroptosis execution. Therefore, ACSL4 inhibitors are emerging as attractive anti-ferroptotic agents. Herein, we developed a robust screening cascade with orthogonal biophysical and biochemical techniques to identify original human ACSL4 inhibitors. By screening an FDA-approved drug library, we were able to identify and validate new inhibitors with micromolar-range activities against ACSL4. With an IC50 of 280 nM against hACSL4, antifungal agent sertaconazole is to our knowledge, the most potent ACSL4 inhibitor identified so far. In addition, sertaconazole significantly reduced lipid peroxidation and ferroptosis in human differentiated dopaminergic neurons (Lund human mesencephalic LUHMES cells), demonstrating that it is a valuable chemical tool for further investigating the role of ACSL4 in ferroptosis. This study highlights the phenethyl-imidazole scaffold as a novel and promising starting point for the development of anti-ferroptotic agents targeting ACSL4.
摘要：
Ferroptosis,首次创造于2012年，是一种铁依赖性调节性细胞死亡（RCD），其特征是脂质过氧化物积累到毒性水平。该机制目前正在被评估为多种疾病的靶标，为药物设计和开发提供了新的机会。最近的报道发现酰基辅酶A合成酶长链4（ACSL4）是铁凋亡执行的关键贡献者。因此,ACSL4抑制剂正在成为有吸引力的抗铁剂。在这里，我们利用正交生物物理和生化技术开发了一种稳健的筛选级联,以鉴定原始的人ACSL4抑制剂.通过筛选FDA批准的药物库，我们能够鉴定和验证针对ACSL4具有微摩尔范围活性的新型抑制剂.据我们所知，抗真菌剂舍他康唑对hACSL4的IC50为280nM，迄今为止确定的最有效的ACSL4抑制剂。此外,sertaconazole显著降低人分化多巴胺能神经元（隆德人中脑LUHMES细胞）的脂质过氧化和铁凋亡，证明它是进一步研究ACSL4在铁凋亡中的作用的有价值的化学工具。这项研究强调了苯乙基-咪唑支架作为开发靶向ACSL4的抗铁凋亡剂的新颖且有希望的起点。
