Abstract：
Covalent drug discovery has experienced a renaissance, with numerous electrophilic small molecules recently gaining FDA approval. Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019. Emerging evidence supports additional pharmacological classes of XPO1 modulators targeting Cys528, including the selective inhibitors of transcriptional activation (SITAs) and probes that induce rapid degradation of XPO1. Here, we analyzed structure-activity relationships across multiple structural series of XPO1 Cys528-targeting probes. We observe that the electrophilic moiety of Cys528-targeting small molecules plays a decisive role in the cellular behavior observed, with subtle changes in electrophile structure being sufficient to convert XPO1-targeting probes to different pharmacological classes. This investigation represents a unique case study in which the electrophile functionality used to target a specific cysteine determines the pharmacological effect among diverse XPO1-targeting small molecules.
摘要：
共价药物的发现经历了复兴，许多亲电子小分子最近获得FDA批准。许多结构不同的亲电子小分子靶向半胱氨酸528处的exportin-1（XPO1/CRM1），包括核输出（SINE）selinexor的选择性抑制剂，2019年被FDA批准为抗癌药物。新兴证据支持靶向Cys528的XPO1调节剂的其他药理学类别，包括选择性转录激活抑制剂（SITAs）和诱导XPO1快速降解的探针。这里,我们分析了XPO1Cys528靶向探针的多个结构系列的结构-活性关系。我们观察到Cys528靶向小分子的亲电子部分在观察到的细胞行为中起决定性作用，亲电结构的细微变化足以将XPO1靶向探针转化为不同的药理学类别。这项研究代表了一个独特的案例研究，其中用于靶向特定半胱氨酸的亲电功能决定了多种靶向XPO1的小分子的药理作用。
