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

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.

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.

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.