低氧诱导因子2α抑制剂的发现及其在肾癌治疗中的应用潜力

Discovery of Hypoxia-inducible Factor 2αInhibitors and Their Potential in The Treatment of Renal Cell Carcinoma

氧对生物成长和发育至关重要,但低氧适应在许多生理和病理过程也发挥关键作用。常氧时,低氧诱导因子2α(HIF-2α)可被肿瘤抑制蛋白VHL泛素化修饰,进一步被蛋白酶体迅速降解;低氧时,HIF-2α不再降解,从而进入细胞核与HIF-β亚基形成异二聚体并激活靶基因表达。肾癌通常存在高频VHL基因失活而导致HIF-2α积累,最终促使肾癌发生发展。因此,HIF-2α被看作肾癌治疗的新靶点。尽管HIF-2α被视为“不可成药”分子,但仍成功开发变构抑制剂PT2385和PT2977,它们通过特异性拮抗HIF-2α/HIF-1β异二聚体形成发挥药理作用。临床前和临床试验表明,与标准药物相比,HIF-2α抑制剂在肾癌治疗方面效果更理想、耐受性更强。这些进展意味着HIF-2α抑制剂有望在肾癌临床治疗方面发挥重要作用。

Oxygen is essential for life growth and development,but hypoxia adaptation is also important in many physiological and pathological processes.At normal oxygen levels,hypoxia-inducible factor 2α(HIF-2α)is ubiquitinated by von Hippel-Lindau(VHL)and then rapidly degraded by the proteasome.Under hypoxia,HIF-2αis not degraded and enters the nucleus to form heterodimers with HIF-βsubunit,and then activate target genes’expression.Renal cell carcinoma(RCC)usually has high-frequency VHL gene inactivation,which leads to the accumulation of HIF-2αand ultimately promotes the initiation and progression of RCC.So,HIF-2αcan act as a new therapeutic target in RCC.Although HIF-2αis generally regarded as"undruggable",the allosteric inhibitors PT2385/PT2977 have been successfully developed,which perform pharmacological effects by specifically antagonizing the formation of HIF-2α/HIF-1βheterodimers.Based on the structure of HIF-2α/HIF-1βheterodimers,an extensive screening of small-molecule libraries was performed and 130 potential HIF-2αinhibitors were generated.After further considering the potency,selectivity and oral viability,PT2385 and PT2977 were chosen,in which PT2385 for in vitro studies and PT2977 for clinical development.PT2977 can selectively inhibit the expression of HIF-2αtargeted genes in cultured RCC cells,but do not affect HIF-1αtargeted genes.Preclinical and clinical trials have demonstrated that HIF-2αinhibitors are effective in blocking cancer cell growth,proliferation,and tumor regression in RCC.These data also indicated that these inhibitors are more effective and better tolerated and have few side effects than standard drugs in treating RCC.Prolonged HIF-2αinhibitors treatment can also produce drug resistance,which can be partly attributed to key amino acid mutations in binding domain of HIF-2αto inhibitors.These advances mean that HIF-2αallosteric inhibitors are expected to play an important role in the clinical treatment of RCC.