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HIF-2α-IN-1 Sale

目录号 : GC31358

HIF-2α-IN-1是一种HIF-2α抑制剂,IC50值小于500nM。

HIF-2α-IN-1 Chemical Structure

Cas No.:1799948-06-3

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥3,651.00
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1mg
¥1,755.00
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5mg
¥4,680.00
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10mg
¥6,930.00
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25mg
¥12,284.00
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Sample solution is provided at 25 µL, 10mM.

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产品描述

HIF-2α-IN-1 is a HIF-2α inhibitor has an IC50 of less than 500 nM in HIF-2α scintillation proximity assay.IC50 value: < 500 nMTarget: HIF-2α

[1]. Bruick Richard Keith, et al. HIF-2α inhibitors for treating iron overload disorders. From PCT Int. Appl. (2016), WO 2016057242 A1 20160414. [2]. Dixon Darryl David, et al. Preparation of cyclic sulfone and sulfoximine analogs as HIF-2α inhibitors. From PCT Int. Appl. (2015), WO 2015095048 A1 20150625.

Chemical Properties

Cas No. 1799948-06-3 SDF
Canonical SMILES N#CC1=CC(F)=CC(OC2=CC=C3C([C@@H](O)C(F)(F)S3(=O)=O)=C2C(F)F)=C1
分子式 C16H8F5NO4S 分子量 405.3
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 2.4673 mL 12.3365 mL 24.6731 mL
5 mM 0.4935 mL 2.4673 mL 4.9346 mL
10 mM 0.2467 mL 1.2337 mL 2.4673 mL
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Research Update

HIF-1 and HIF-2 transcription factors--similar but not identical

Hypoxia inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors mediating the cellular response to hypoxia. Recent data indicate that not only ubiquitous HIF-1 alpha, but also more cell-specific HIF-2 alpha, is an important regulator of the hypoxia response. Although both alpha subunits are highly conservative at protein level, share similar domain structure, heterodimerize with HIF-1 beta, and bind to the same DNA sequence called hypoxia responsive element (HRE), their effect on the expression of some genes may vary. In this review we stressed the differences between the isoforms, their structure and expression pattern. Moreover, we described diversity of coactivators and proteins which interact with HIFs, and which are responsible for the specificity of their action. Finally, recent data showing link between HIFs and specific microRNA have been presented.

The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy

Introduction: Hypoxia is one of the intrinsic features of solid tumors, and it is always associated with aggressive phenotypes, including resistance to radiation and chemotherapy, metastasis, and poor patient prognosis. Hypoxia manifests these unfavorable effects through activation of a family of transcription factors, Hypoxia-inducible factors (HIFs) play a pivotal role in the adaptation of tumor cells to hypoxic and nutrient-deprived conditions by upregulating the transcription of several pro-oncogenic genes. Several advanced human cancers share HIFs activation as a final common pathway. Areas covered: This review highlights the role and regulation of the HIF-1/2 in cancers and alludes on the biological complexity and redundancy of HIF-1/2 regulation. Moreover, this review summarizes recent insights into the therapeutic approaches targeting the HIF-1/2 pathway. Expert opinion: More studies are needed to unravel the extensive complexity of HIFs regulation and to develop more precise anticancer treatments. Inclusion of HIF-1/2 inhibitors to the current chemotherapy regimens has been proven advantageous in numerous reported preclinical studies. The combination therapy ideally should be personalized based on the type of mutations involved in the specific cancers, and it might be better to include two drugs that inhibit HIF-1/2 activity by synergistic molecular mechanisms.

Targeting renal cell carcinoma with a HIF-2 antagonist

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1β) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1β, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.

HIF-2 in Cancer-Associated Fibroblasts Polarizes Macrophages and Creates an Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

Primary endothelial cell-specific regulation of hypoxia-inducible factor (HIF)-1 and HIF-2 and their target gene expression profiles during hypoxia

During hypoxia, a cellular adaptive response activates hypoxia-inducible factors (HIFs; HIF-1 and HIF-2) that respond to low tissue-oxygen levels and induce the expression of a number of genes that promote angiogenesis, energy metabolism, and cell survival. HIF-1 and HIF-2 regulate endothelial cell (EC) adaptation by activating gene-signaling cascades that promote endothelial migration, growth, and differentiation. An HIF-1 to HIF-2 transition or switch governs this process from acute to prolonged hypoxia. In the present study, we evaluated the mechanisms governing the HIF switch in 10 different primary human ECs from different vascular beds during the early stages of hypoxia. The studies demonstrate that the switch from HIF-1 to HIF-2 constitutes a universal mechanism of cellular adaptation to hypoxic stress and that HIF1A and HIF2A mRNA stability differences contribute to HIF switch. Furthermore, using 4 genome-wide mRNA expression arrays of HUVECs during normoxia and after 2, 8, and 16 h of hypoxia, we show using bioinformatics analyses that, although a number of genes appeared to be regulated exclusively by HIF-1 or HIF-2, the largest number of genes appeared to be regulated by both.-Bartoszewski, R., Moszyńska, A., Serocki, M., Cabaj, A., Polten, A., Ochocka, R., Dell'Italia, L., Bartoszewska, S., Króliczewski, J., D?browski, M., Collawn, J. F. Primary endothelial cell-specific regulation of hypoxia-inducible factor (HIF)-1 and HIF-2 and their target gene expression profiles during hypoxia.