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Discovery of Novel Potent Covalent Glutathione Peroxidase 4 Inhibitors as Highly Selective Ferroptosis Inducers for the Treatment of Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-07-15 , DOI: 10.1021/acs.jmedchem.3c00967
Tingting Chen 1 , Jiafu Leng 1 , Jun Tan 1 , Yongjun Zhao 1 , Shanshan Xie 1 , Shifang Zhao 1 , Xiangyu Yan 1 , Liqiao Zhu 1 , Jun Luo 1 , Lingyi Kong 1 , Yong Yin 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-07-15 , DOI: 10.1021/acs.jmedchem.3c00967
Tingting Chen 1 , Jiafu Leng 1 , Jun Tan 1 , Yongjun Zhao 1 , Shanshan Xie 1 , Shifang Zhao 1 , Xiangyu Yan 1 , Liqiao Zhu 1 , Jun Luo 1 , Lingyi Kong 1 , Yong Yin 1
Affiliation
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Glutathione peroxidase 4 (GPX4) is a promising target to induce ferroptosis for the treatment of triple-negative breast cancer (TNBC). We designed and synthesized a novel series of covalent GPX4 inhibitors based on RSL3 and ML162 by structural integration and simplification strategies. Among them, compound C18 revealed a remarkable inhibitory activity against TNBC cells and significantly inhibited the activity of GPX4 compared to RSL3 and ML162. Moreover, it was identified that C18 could notably induce ferroptosis with high selectivity by increasing the accumulation of lipid peroxides (LPOs) in cells. Further study demonstrated that C18 covalently bound to the Sec46 of GPX4. Surprisingly, C18 exhibited an outstanding potency of tumor growth inhibition in the MDA-MB-231 xenograft model with a TGI value of 81.0%@20 mg/kg without obvious toxicity. Overall, C18 could be a promising GPX4 covalent inhibitor to induce ferroptosis for the treatment of TNBC.
中文翻译：
发现新型强效共价谷胱甘肽过氧化物酶 4 抑制剂作为高选择性铁死亡诱导剂用于治疗三阴性乳腺癌
谷胱甘肽过氧化物酶 4 (GPX4) 是诱导铁死亡治疗三阴性乳腺癌 (TNBC) 的一个有前景的靶点。我们通过结构整合和简化策略，设计并合成了基于RSL3和ML162的一系列新型共价GPX4抑制剂。其中，化合物C18对TNBC细胞表现出显着的抑制活性，并且与RSL3和ML162相比，显着抑制GPX4的活性。此外，还发现C18可以通过增加细胞中脂质过氧化物（LPO）的积累来高选择性地显着诱导铁死亡。进一步研究表明C18与GPX4的Sec46共价结合。令人惊讶的是，C18在MDA-MB-231异种移植模型中表现出出色的肿瘤生长抑制效力，TGI值为81.0%@20 mg/kg，且没有明显毒性。总体而言，C18可能是一种有前景的 GPX4 共价抑制剂，可诱导铁死亡，用于治疗 TNBC。
更新日期：2023-07-15
中文翻译：
发现新型强效共价谷胱甘肽过氧化物酶 4 抑制剂作为高选择性铁死亡诱导剂用于治疗三阴性乳腺癌
谷胱甘肽过氧化物酶 4 (GPX4) 是诱导铁死亡治疗三阴性乳腺癌 (TNBC) 的一个有前景的靶点。我们通过结构整合和简化策略，设计并合成了基于RSL3和ML162的一系列新型共价GPX4抑制剂。其中，化合物C18对TNBC细胞表现出显着的抑制活性，并且与RSL3和ML162相比，显着抑制GPX4的活性。此外，还发现C18可以通过增加细胞中脂质过氧化物（LPO）的积累来高选择性地显着诱导铁死亡。进一步研究表明C18与GPX4的Sec46共价结合。令人惊讶的是，C18在MDA-MB-231异种移植模型中表现出出色的肿瘤生长抑制效力，TGI值为81.0%@20 mg/kg，且没有明显毒性。总体而言，C18可能是一种有前景的 GPX4 共价抑制剂，可诱导铁死亡，用于治疗 TNBC。
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