PT2977 is an orally active and selective HIF-2α inhibitor with an IC50 of 9nM[1]. HIF-2α is a key transcription factor regulating the expression of hypoxia response genes and plays a core role in tumor angiogenesis, stem cell maintenance and metabolic reprogramming[2]. PT2977 blocks the transcription of downstream target genes by inhibiting HIF-2α, and is mainly used in research for the treatment of clear cell renal cell carcinoma (ccRCC)[3].
In vitro, PT2977 (2μM; 48h) inhibited the dimerization of HIF-2α with HIF-1β in 786-O and A498 renal cancer cell lines, reduced the mRNA levels of VEGFA, GLUT1, and Cyclin D1, and blocked clonogenic formation in soft agar[4]. PT2977 (0-2μM; 24h) reduced the mRNA levels of HIF target genes without significant effect on cell proliferation[5].
In vivo, PT2977 (100mg/kg; p.o.; twice daily; 28 days) decreased tumor volume, reduced circulating human(graft-derived) VEGF levels, and lowered the mRNA levels of HIF-2α target genes (such as VEGFA, CCND1, GLUT1, PAI1, and CXCR4) in a 786-O cell line-derived xenograft mouse model[6]. PT2977 (30mg/kg or 100mg/kg; p.o.; twice daily; 5 days) decreased HIF-2α and Cyclin D1 protein levels, increased the number of active Caspase-3 positive cells, and promoted the apoptosis of tumor cells in tumor tissues of ccRCC xenograft tumor models[7].
References:
[1] Xu R, Wang K, Rizzi JP, et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma. J Med Chem. 2019;62(15):6876-6893.
[2] Murugesan T, Rajajeyabalachandran G, Kumar S, Nagaraju S, Jegatheesan SK. Targeting HIF-2α as therapy for advanced cancers. Drug Discov Today. 2018;23(7):1444-1451.
[3] Wu X, Lazris D, Wong R, Tykodi SS. Belzutifan for the treatment of renal cell carcinoma. Ther Adv Med Oncol. 2025;17:17588359251317846.
[4] Hamal KB, Pavlich CI, Carlson GJ, et al. Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches. Tetrahedron Lett. 2023;128:154691.
[5] Cho H, Du X, Rizzi JP, et al. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature. 2016;539(7627):107-111.
[6] Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112-117.
[7] Wallace, E. M., Rizzi, J. P., Hanrahan, C. F., et al. A small-molecule antagonist of HIF-2α is efficacious in preclinical models of renal cell carcinoma.
PT2977是一种口服有效的、选择性的HIF-2α抑制剂，其IC50为9nM[1]。HIF-2α是一个关键的转录因子，调节缺氧反应基因的表达，在肿瘤血管生成、干细胞维持和代谢重编程中发挥核心作用[2]。PT2977通过抑制HIF-2α来阻断下游靶基因的转录，主要用于治疗透明细胞肾细胞癌（ccRCC）的研究[3]。
在体外，PT2977（2μM；48小时）在786-O和A498肾癌细胞系中抑制了 HIF-2α与HIF-1β的二聚化，降低了VEGFA、GLUT1和Cyclin D1的mRNA水平，并阻断了软琼脂中的克隆形成能力[4]。PT2977（0-2μM；24小时）在786-O细胞系中降低了HIF靶基因的mRNA水平，但对细胞增殖无显著影响[5]。
在体内，PT2977（100mg/kg；口服；每天两次；28天）在786-O细胞系来源的异种移植小鼠模型中减少了肿瘤体积，降低了循环中人（移植来源）VEGF水平，并降低了HIF-2α靶基因（如 VEGFA、CCND1、GLUT1、PAI1 和 CXCR4）的mRNA 水平[6]。PT2977（30mg/kg 或 100mg/kg；口服；每天两次；5天）在ccRCC异种移植肿瘤模型中降低了肿瘤组织中HIF-2α和Cyclin D1蛋白的水平，增加了活性Caspase-3阳性细胞的数量，并促进了肿瘤细胞凋亡[7]。