3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2 alpha (HIF-2 alpha) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

Xu Rui; Wang Keshi; Rizzi James P.; Huang Heli; Grina Jonas A.; Schlachter Stephen T.; Wang Bin; Wehn Paul M.; Yang Hanbiao; Dixon Darryl D.; Czerwinski Robert M.; Du Xinlin; Ged Emily L.; Han Guangzhou; Tan Huiling; Wong Tai; Xie Shanhai; Josey John A.; Wallace Eli M.

首页> 外文期刊>Journal of Medicinal Chemistry >3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2 alpha (HIF-2 alpha) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

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3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2 alpha (HIF-2 alpha) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

机译：3 - [（1S，2S，3R）-2,3-二氟-1-羟基-7-甲基磺酰基茚满-4-基]氧 - 5-氟苯苄腈（PT2977），一种缺氧诱导因子2α（HIF-2α ）用于治疗透明细胞肾细胞癌的抑制剂

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The hypoxia-inducible factor 2 alpha (HIF-2 alpha) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2 alpha inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2 alpha inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.

机译：缺氧诱导因子2α（HIF-2α）是透明细胞肾细胞癌（CCRCC）的关键致癌钳。我们的第一个HIF-2α抑制剂PT2385展示了大量预处理先进的CCRCC患者在临床临床活动中的有希望的证据。然而，PT2385受到PT2385广泛代谢的可变和剂量限制药代动力学的限制为其葡萄糖醛酸代谢物。在此，我们描述了通过减少相2代谢而获得的增强效力和改善的药代动力学曲线的第二代HIF-2α抑制剂PT2977的发现。通过将PT2385中的孪生二氟基改变为邻近的二氟基团的结构改性导致增强效力，降脂脂肪性降低，药代动力学性质显着改善。在1期剂量升级研究中，PT2977的临床药代动力学支持假设，即减少葡糖醛酸速会改善暴露并降低患者的可变性。临床活动的早期证据显示PT2977在治疗CCRCC中的承诺。

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来源
《Journal of Medicinal Chemistry》 |2019年第15期|共18页
作者
Xu Rui; Wang Keshi; Rizzi James P.; Huang Heli; Grina Jonas A.; Schlachter Stephen T.; Wang Bin; Wehn Paul M.; Yang Hanbiao; Dixon Darryl D.; Czerwinski Robert M.; Du Xinlin; Ged Emily L.; Han Guangzhou; Tan Huiling; Wong Tai; Xie Shanhai; Josey John A.; Wallace Eli M.;
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Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

Peloton Therapeut Inc 2330 Inwood Rd Suite 226 Dallas TX 75235 USA;

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1. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2 alpha (HIF-2 alpha) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma [J] . Xu Rui, Wang Keshi, Rizzi James P., Journal of Medicinal Chemistry . 2019,第15期

机译：3 - [（1S，2S，3R）-2,3-二氟-1-羟基-7-甲基磺酰基茚满-4-基]氧 - 5-氟苯苄腈（PT2977），一种缺氧诱导因子2α（HIF-2α ）用于治疗透明细胞肾细胞癌的抑制剂
2. Design and Activity of Specific Hypoxia-Inducible Factor-2 alpha (HIF-2 alpha) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385) [J] . Wehn Paul M., Rizzi James P., Dixon Darryl D., Journal of Medicinal Chemistry . 2018,第21期

机译：特异性缺氧诱导因子-2α（HIF-2α）抑制剂的设计和活性治疗透明细胞肾细胞癌：临床候选物的发现-3 - （（2,2-二氟-1-羟基 -7-（甲基磺酰基）-2,3-二氢-1H-茚 - 4-基）氧基）-5-氟苯腈（PT2385）
3. Design and Activity of Specific Hypoxia-Inducible Factor-2 alpha (HIF-2 alpha) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385) [J] . Wehn Paul M., Rizzi James P., Dixon Darryl D., Journal of Medicinal Chemistry . 2018,第21期

机译：特异性缺氧诱导因子-2α（HIF-2α）抑制剂的设计和活性治疗透明细胞肾细胞癌：临床候选物的发现-3 - （（2,2-二氟-1-羟基 -7-（甲基磺酰基）-2,3-二氢-1H-茚 - 4-基）氧基）-5-氟苯腈（PT2385）
4. Expression of Hypoxia-Inducible Factor-1 Alpha in Oral Squamous Cell Carcinoma [C] . Noguchi Natsuyo, Kawashiri Shuichi, Kato Koroku, European Association of Cranio-Maxillo-Facial Surgery . 2010

机译：口腔鳞状细胞癌中缺氧诱导因子-1α的表达
5. The role of protein kinases in hypoxia-inducible factor 1-alpha induced erythropoietin gene expression in hepatocellular carcinoma (Hep3B) cells. [D] . Gutierrez Figueroa, Yanira. 2004

机译：蛋白激酶在肝细胞癌（Hep3B）细胞中的缺氧诱导因子1-α诱导的促红细胞生成素基因表达中的作用。
6. Differential Regulation of the Transcriptional Activities of Hypoxia-Inducible Factor 1 Alpha (HIF-1α) and HIF-2α in Stem Cells [O] . Cheng-Jun Hu, Sangeeta Iyer, Aneesa Sataur, 2006

机译：缺氧诱导因子1α（HIF-1α）和HIF-2α在干细胞中转录活性的差异调节。
7. 3-(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yloxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma [O] . Rui Xu, Keshi Wang, James P. Rizzi, 2019

机译：3 - （1S，2S，3R）-2,3-二氟-1-羟基-7-甲基磺酰突-4-基氧 - 5-氟苯苄腈（PT2977），一种缺氧诱导因子2α（HIF-2α）抑制剂用于治疗透明细胞肾细胞癌

3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2 alpha (HIF-2 alpha) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

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