Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility.
Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility.
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DOI：
10.1016/j.bmcl.2015.07.018
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发表时间：
2015-11-01
影响因子：
2.7
通讯作者：
Stockwell BR
中科院分区：
文献类型：
--
作者：
Larraufie MH;Yang WS;Jiang E;Thomas AG;Slusher BS;Stockwell BR
在没有亲电官能团的支架上引入反应性羰基来生成可逆的共价抑制剂是提高化合物效力的潜在有用策略。然而，醛在代谢上是不稳定的，这就排除了在动物模型或人类临床研究中使用这种策略进行化合物测试的可能性。为了克服这一限制，我们设计了基于酮的官能团，能够形成可逆的共价加合物，同时表现出高的代谢稳定性，并赋予其悬垂支架更好的水溶性。我们在铁下垂诱导剂和实验性治疗擦除素上测试了这一策略，并观察到复合效力的大幅增加。特别是，一种新的羰基Erastin类似物，称为IKE，表现出更好的效力、溶解性和代谢稳定性，因此代表着未来在体内癌症治疗应用的理想候选。
Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate future in vivo cancer therapeutic applications.