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Small-molecule inhibitors of the HIF pathway and synthetic lethal interactions

机译：HIF途径的小分子抑制剂和合成致死相互作用

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Introduction: Activation of the hypoxia response pathway is a feature of many tumours and is one of the key mechanisms associated with tumour growth, chemoresistance and radioresistance. The major component of the hypoxia response pathway is the heterodimeric transcription factor, hypoxia-inducible factor (HIF), which is upregulated in many human cancers. Therefore, HIF is an attractive therapeutic target and several strategies have been developed to target it. Areas covered: Approaches used in targeting the hypoxia response pathway are discussed. Reviewed are agents that target upstream, directly and downstream of HIF, as well as some of the challenges in HIF-targeted therapy. Expert opinion: Many of the therapeutic agents that are in clinical use inhibit downstream HIF target genes, but ideally a molecule specific to HIF will have a more potent effect in inhibiting multiple HIF pathways. However, many anti-HIF molecules have multiple targets, which may increase non-specific cytotoxicity. In addition, many anti-HIF agents cannot discriminate between the different isoforms of HIF-α. So, it is important to assess whether targeting both HIF-1α and HIF-2α or each subunit selectively will provide better therapeutic effects.
机译：简介：缺氧反应途径的激活是许多肿瘤的特征，并且是与肿瘤生长，化学抗性和放射抗性相关的关键机制之一。缺氧应答途径的主要成分是异二聚体转录因子，低氧诱导因子（HIF），在许多人类癌症中均被上调。因此，HIF是有吸引力的治疗靶标，并且已经开发了针对其的几种策略。涵盖的领域：讨论了针对低氧反应途径的方法。审查的是针对HIF上游，直接和下游的药物，以及针对HIF的治疗中的一些挑战。专家意见：临床上使用的许多治疗剂均可抑制下游的HIF靶基因，但理想情况下，对HIF特异的分子在抑制多种HIF途径方面将具有更有效的作用。但是，许多抗HIF分子具有多个靶标，这可能会增加非特异性细胞毒性。此外，许多抗HIF药物无法区分HIF-α的不同同工型。因此，评估靶向HIF-1α和HIF-2α或选择性地靶向每个亚基是否将提供更好的治疗效果非常重要。

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