PT2977
(Synonyms: PT2977; MK-6482) 目录号 : GC37034
PT2977是一种口服有效的、选择性的HIF-2α抑制剂，其IC50为9nM。
Cas No.:1672668-24-4
Sample solution is provided at 25 µL, 10mM.
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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]。
| Cell experiment [1]: | |
Cell lines | 786-O renal cancer cells |
Preparation Method | 2×105 786-O renal cancer cells were inoculated per well in 6-well plates with 3 replicates for each group. Cells were treated with 2μM PT2977 for 48 hours. Negative control group was not treated with anything. After 48 hours, cells were harvested, and RNA was extracted using TRIzol reagent following manufacturer’s instructions. RT-PCR was then performed. |
Reaction Conditions | 2μM; 48h |
Applications | PT2977 (2μM; 48h) reduced the mRNA levels of VEGFA, GLUT1, and Cyclin D1 in 786-O renal cancer cell lines. |
| Animal experiment [2]: | |
Animal models | NOD/SCID mice |
Preparation Method | 64mm3 fragments of tissue from stably growing orthotopic tumorgrafts were implanted subcutaneously in 4–6 week old female and male NOD/SCID mice. Vehicle (10% EtOH, 30% PEG400, 60% MCT [0.5% methyl cellulose, 0.5% Tween 80 (aq)]) was administered by gavage every 12h. PT2977 was administered at 100 mg/kg by oral gavage every 12h in 10% EtOH, 30% PEG400, 60% MCT for 28 consecutive days. Mouse weights were taken weekly. Tumors were generally measured twice a week using a digital caliper. |
Dosage form | 100mg/kg; p.o.; twice daily; 28 days |
Applications | PT2977 (100mg/kg; p.o.; twice daily; 28 days) decreased tumor volume in a 786-O cell line-derived xenograft mouse model. |
References: | |
| Cas No. | 1672668-24-4 | SDF | |
| 别名 | PT2977; MK-6482 | ||
| Canonical SMILES | N#CC1=CC(F)=CC(OC2=CC=C(S(=O)(C)=O)C3=C2[C@@H](F)[C@@H](F)[C@H]3O)=C1 | ||
| 分子式 | C17H12F3NO4S | 分子量 | 383.34 |
| 溶解度 | DMSO: 50 mg/mL (130.43 mM) | 储存条件 | Store at -20°C, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6087 mL | 13.0433 mL | 26.0865 mL |
| 5 mM | 521.7 μL | 2.6087 mL | 5.2173 mL |
| 10 mM | 260.9 μL | 1.3043 mL | 2.6087 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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- Purity: >98.00%
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