Structure-activity relationships of GPX4 inhibitor warheads.
Structure-activity relationships of GPX4 inhibitor warheads.
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DOI：
10.1016/j.bmcl.2020.127538
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发表时间：
2020-12-01
影响因子：
2.7
通讯作者：
Schreiber SL
中科院分区：
文献类型：
--
作者：
Eaton JK;Furst L;Cai LL;Viswanathan VS;Schreiber SL
GPX4的直接抑制需要共价修饰活性位点的硒代半胱氨酸。虽然表型筛选表明，活化的烷基氯和掩蔽的腈氧化物可以抑制GPX4共价，潜在的亲电子弹头的能力，抑制细胞GPX4的系统评估一直缺乏。在这里，我们调查了超过25个亲电子弹头在几个不同的GPX 4靶向支架。我们发现，与氯乙酰胺相比，亲电试剂的反应性减弱，无法抑制GPX 4，尽管预期的亲核性的硒代半胱氨酸残基。然而，我们在这项研究中发现的高反应性丙炔酰胺可以替代GPX4抑制剂中的氯乙酰胺和硝基异恶唑弹头。我们的观察结果表明，亲电掩蔽策略，包括我们描述的丙炔酰胺和氮氧化物为基础的弹头，可能是有前途的改进的共价GPX4抑制剂的发展。
Direct inhibition of GPX4 requires covalent modification of the active-site selenocysteine. While phenotypic screening has revealed that activated alkyl chlorides and masked nitrile oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here, we survey more than 25 electrophilic warheads across several distinct GPX4-targeting scaffolds. We find that electrophiles with attenuated reactivity compared to chloroacetamides are unable to inhibit GPX4 despite the expected nucleophilicity of the selenocysteine residue. However, highly reactive propiolamides we uncover in this study can substitute for chloroacetamide and nitroisoxazole warheads in GPX4 inhibitors. Our observations suggest that electrophile masking strategies, including those we describe for propiolamide- and nitrile-oxide-based warheads, may be promising for the development of improved covalent GPX4 inhibitors.
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