**10.4 HIF-2 inhibitors**

The finding that HIF-1α and HIF-2α have opposing effects on the pathogenesis of ccRCC initiated efforts to generate isoform-specific inhibitors. This led to the development of small molecule inhibitors that specifically prevent HIF-2α dimerizing with HIF-1β, thereby blocking HIF-2α -dependent transcription without affecting HIF-1α activity [148]. These inhibitors would be predicted to have greater efficacy compared to targeting both isoforms simultaneously, whilst reducing off-target side-effects. Indeed, investigation of these compounds as potential ccRCC treatments, both in animal models of ccRCC and early clinical trials, have yielded promising results [149–151]. Therefore, these compounds could provide another strategy for treating metastatic ccRCC.
