Discovery of Hypoxia-inducible Factor2?Inhibitors and Their Potential in TheTreatment of Renal Cell Carcinoma

Oxygen is essential for life growth and development,but hypoxia adaptation is also important in manyphysiological and pathological processes.At normal oxygen levels,hypoxia-inducible factor2 alpha(HIF-2 alpha)isubiquitinated by von Hippel-Lindau(VHL)and then rapidly degraded by the proteasome.Under hypoxia,HIF-2 alpha is not degraded and enters the nucleus to form heterodimers with HIF-beta subunit,and then activate target genes'expression.Renal cell carcinoma(RCC)usually has high-frequencyVHLgene inactivation,which leads to theaccumulation of HIF-2 alpha and ultimately promotes the initiation and progression of RCC.So,HIF-2 alpha can act as anew therapeutic target in RCC.Although HIF-2 alpha is generally regarded as"undruggable",the allosteric inhibitorsPT2385/PT2977have been successfully developed,which perform pharmacological effects by specificallyantagonizing the formation of HIF-2 alpha/HIF-1 beta heterodimers.Based on the structure of HIF-2 alpha/HIF-1 beta heterodimers,an extensive screening of small-molecule libraries was performed and130potential HIF-2 alpha inhibitors were generated.After further considering the potency,selectivity and oral viability,PT2385andPT2977were chosen,in which PT2385forin vitrostudies and PT2977for clinical development.PT2977canselectively inhibit the expression of HIF-2 alpha targeted genes in cultured RCC cells,but do not affect HIF-1 alpha targeted genes.Preclinical and clinical trials have demonstrated that HIF-2 alpha inhibitors are effective in blockingcancer cell growth,proliferation,and tumor regression in RCC.These data also indicated that these inhibitors aremore effective and better tolerated and have few side effects than standard drugs in treating RCC.ProlongedHIF-2 alpha inhibitors treatment can also produce drug resistance,which can be partly attributed to key amino acidmutations in binding domain of HIF-2 alpha to inhibitors.These advances mean that HIF-2 alpha allosteric inhibitors areexpected to play an important role in the clinical treatment of RCC