Two decades of research have proven the relevance of ion channel expression for tumor progression in virtually every indication, and it has become clear that inhibition of specific ion channels will eventually become part of the oncology therapeutic arsenal. However, ion channels play relevant roles in all aspects of physiology, and specificity for the tumor tissue remains a challenge to avoid undesired effects. Eag1 (K_V10.1) is a voltage-gated potassium channel whose expression is very restricted in healthy tissues outside of the brain, while it is overexpressed in 70% of human tumors. Inhibition of Eag1 reduces tumor growth, but the search for potent inhibitors for tumor therapy suffers from the structural similarities with the cardiac HERG channel, a major off-target. Existing inhibitors show low specificity between the two channels, and screenings for Eag1 binders are prone to enrichment in compounds that also bind HERG. Rational drug design requires knowledge of the structure of the target and the understanding of structure–function relationships. Recent studies have shown subtle structural differences between Eag1 and HERG channels with profound functional impact. Thus, although both targets' structure is likely too similar to identify leads that exclusively bind to one of the channels, the structural information combined with the new knowledge of the functional relevance of particular residues or areas suggests the possibility of selective targeting of Eag1 in cancer therapies. Further development of selective Eag1 inhibitors can lead to first-in-class compounds for the treatment of different cancers.

中文翻译：

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通过合理设计克服 HERG 钾通道责任的挑战：用于癌症治疗的 Eag1 抑制剂

二十年的研究已经证明了离子通道表达与几乎所有适应症中的肿瘤进展的相关性，并且很明显，抑制特定离子通道最终将成为肿瘤治疗库的一部分。然而，离子通道在生理学的各个方面都发挥着相关作用，并且对肿瘤组织的特异性仍然是避免不良影响的挑战。Eag1 (K _V10.1) 是一种电压门控钾通道，其在脑外健康组织中的表达非常有限，而在 70% 的人类肿瘤中过度表达。抑制 Eag1 可减少肿瘤生长，但寻找有效的肿瘤治疗抑制剂受到与心脏 HERG 通道（一种主要的脱靶）结构相似性的影响。现有的抑制剂在两个通道之间表现出低特异性，筛选 Eag1 结合剂容易富集也结合 HERG 的化合物。合理的药物设计需要了解靶点的结构和了解结构-功能关系。最近的研究表明 Eag1 和 HERG 通道之间的细微结构差异具有深远的功能影响。因此，尽管这两个目标 结构可能过于相似，无法识别仅与其中一个通道结合的线索，结构信息与特定残基或区域功能相关性的新知识相结合，表明在癌症治疗中选择性靶向 Eag1 的可能性。选择性 Eag1 抑制剂的进一步开发可以产生用于治疗不同癌症的一流化合物。