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CETZOLE Analogs as Potent Ferroptosis Inducers and Their Target Identification Using Covalent/Affinity Probes
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-12 , DOI: 10.1021/acs.jmedchem.3c02084 Samkeliso Dlamini 1 , Shahrzad Mohajeri 1 , Nishanth Kuganesan 2 , Shaimaa H Sindi 1 , Endri Karaj 1 , Dewmi S Rathnayake 2 , Jade McDaniel 1 , William R Taylor 2 , L M Viranga Tillekeratne 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-12 , DOI: 10.1021/acs.jmedchem.3c02084 Samkeliso Dlamini 1 , Shahrzad Mohajeri 1 , Nishanth Kuganesan 2 , Shaimaa H Sindi 1 , Endri Karaj 1 , Dewmi S Rathnayake 2 , Jade McDaniel 1 , William R Taylor 2 , L M Viranga Tillekeratne 1
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Ferroptosis is a recently discovered cell death mechanism triggered by iron-dependent elevation of reactive oxygen species leading to lipid membrane peroxidation. We previously reported the development of a new class of ferroptosis inducers referred to as CETZOLEs with CC50 values in the low micromolar range. Structure–activity relationship study of these compounds led to the development of more potent analogs with CC50 values in the nanomolar range. Cells exposed to these compounds displayed the hallmarks of ferroptosis including cell death through ROS accumulation. Cancer cells were found to be more sensitive to these compounds than normal cells. Proteomic studies using covalent and affinity probes led to the identification of cystathionine β-synthase, peroxiredoxins, ADP/ATP carriers, and glucose dehydrogenase as enriched proteins. The binding of CETZOLEs to these proteins as well as GPX4 was validated by Western blotting. This group of proteins is known to be associated with cellular antioxidant pathways.
中文翻译：
CETZOLE 类似物作为有效的铁死亡诱导剂及其使用共价/亲和探针的靶标鉴定
铁死亡是最近发现的一种细胞死亡机制，由活性氧的铁依赖性升高引发，导致脂质膜过氧化。我们之前报道了一类新型铁死亡诱导剂的开发，称为 CETZOLEs，其 CC50 值在低微摩尔范围内。这些化合物的构效关系研究导致了 CC50 值在纳摩尔范围内的更有效类似物的开发。暴露于这些化合物的细胞显示出铁死亡的标志，包括通过 ROS 积累导致的细胞死亡。发现癌细胞比正常细胞对这些化合物更敏感。使用共价和亲和探针的蛋白质组学研究导致将胱硫醚 β-合酶、过氧化物还原蛋白、ADP/ATP 载体和葡萄糖脱氢酶鉴定为富集蛋白。CETZOLE 与这些蛋白质以及 GPX4 的结合通过蛋白质印迹验证。已知这组蛋白质与细胞抗氧化途径有关。
更新日期：2024-09-12
中文翻译：
CETZOLE 类似物作为有效的铁死亡诱导剂及其使用共价/亲和探针的靶标鉴定
铁死亡是最近发现的一种细胞死亡机制，由活性氧的铁依赖性升高引发，导致脂质膜过氧化。我们之前报道了一类新型铁死亡诱导剂的开发，称为 CETZOLEs，其 CC50 值在低微摩尔范围内。这些化合物的构效关系研究导致了 CC50 值在纳摩尔范围内的更有效类似物的开发。暴露于这些化合物的细胞显示出铁死亡的标志，包括通过 ROS 积累导致的细胞死亡。发现癌细胞比正常细胞对这些化合物更敏感。使用共价和亲和探针的蛋白质组学研究导致将胱硫醚 β-合酶、过氧化物还原蛋白、ADP/ATP 载体和葡萄糖脱氢酶鉴定为富集蛋白。CETZOLE 与这些蛋白质以及 GPX4 的结合通过蛋白质印迹验证。已知这组蛋白质与细胞抗氧化途径有关。
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