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IDF-11774 Sale

目录号 : GC32948

IDF-11774 is a hypoxia-inducible factor-1 (HIF-1) inhibitor. It reduces the HRE-luciferase activity of HIF-1α (IC50 = 3.65 μM) and blocks HIF-1α accumulation under hypoxia in HCT116 human colon cancer cells.

IDF-11774 Chemical Structure

Cas No.:1429054-28-3

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10mM (in 1mL DMSO)
¥681.00
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1mg
¥490.00
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5mg
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10mg
¥1,330.00
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50mg
¥5,530.00
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实验参考方法

Animal experiment:

Female Balb/c nude mice are used in this study. Cancer cells are injected subcutaneously into 4- to 6-week-old female Balb/c nude mice to generate tumors (5 mice per group). When the tumors grow to 100 mm3, IDF-11774 is administered orally (per oral) or intravenously for 15 days. Tumor volumes (V) are determined using the following equation: V (mm3)=(length×width×height)×0.5. Percentage tumor growth inhibition (%TGI) values are calculated for each treatment group versus the control[1].

References:

[1]. Ban HS, et al. The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. Cell Death Dis. 2017 Jun 1;8(6):e2843.

产品描述

IDF-11774 is a hypoxia-inducible factor-1 (HIF-1) inhibitor. It reduces the HRE-luciferase activity of HIF-1α (IC50 = 3.65 μM) and blocks HIF-1α accumulation under hypoxia in HCT116 human colon cancer cells.

IDF-11774 inhibits the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. The treatment of IDF-11774 suppresses angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduces glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreases the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Therefore, IDF-11774 reduces cancer cell growth through the regulation of cancer glycolytic metabolism and energy production[1].

IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers[1].

[1] Ban HS, et al. Cell Death Dis. 2017, 8(6):e2843.

Chemical Properties

Cas No. 1429054-28-3 SDF
Canonical SMILES CN1CCN(C(COC2=CC=C(C3(C4)CC5CC4CC(C5)C3)C=C2)=O)CC1
分子式 C23H32N2O2 分子量 368.51
溶解度 DMSO : 60 mg/mL (162.82 mM) 储存条件 Store at -20°C
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1 mM 2.7136 mL 13.5682 mL 27.1363 mL
5 mM 0.5427 mL 2.7136 mL 5.4273 mL
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Research Update

Anti-Tumor Effect of IDF-11774, an Inhibitor of Hypoxia-Inducible Factor-1, on Melanoma

Biomol Ther (Seoul) 2022 Sep 1;30(5):465-472.PMID:35712870DOI:10.4062/biomolther.2022.061.

Melanoma is one of the most aggressive skin cancers. Hypoxia contributes to the aggressiveness of melanoma by promoting cancer growth and metastasis. Upregulation of cyclin D1 can promote uncontrolled cell proliferation in melanoma, whereas stimulation of cytotoxic T cell activity can inhibit it. Epithelial mesenchymal transition (EMT) plays a critical role in melanoma metastasis. Hypoxia-inducible factor-1α (HIF-1α) is a main transcriptional mediator that regulates many genes related to hypoxia. CoCl2 is one of the most commonly used hypoxia-mimetic chemicals in cell culture. In this study, inhibitory effects of IDF-11774, an inhibitor of HIF-1α, on melanoma growth and metastasis were examined using cultured B16F10 mouse melanoma cells and nude mice transplanted with B16F10 melanoma cells in the presence or absence of CoCl2-induced hypoxia. IDF-11774 reduced HIF-1α upregulation and cell survival, but increased cytotoxicity of cultured melanoma cells under CoCl2-induced hypoxia. IDF-11774 also reduced tumor size and local invasion of B16F10 melanoma in nude mice along with HIF-1α downregulation. Expression levels of cyclin D1 in melanoma were increased by CoCl2 but decreased by IDF-11774. Apoptosis of melanoma cells and infiltration of cytotoxic T cells were increased in melanoma after treatment with IDF-11774. EMT was stimulated by CoCl2, but restored by IDF- 11774. Overall, IDF-11774 inhibited the growth and metastasis of B16F10 melanoma via HIF-1α downregulation. The growth of B16F10 melanoma was inhibited by cyclin D1 downregulation and cytotoxic T cell stimulation. Metastasis of B16F10 melanoma was inhibited by EMT suppression.

Identification of Targets of the HIF-1 Inhibitor IDF-11774 Using Alkyne-Conjugated Photoaffinity Probes

Bioconjug Chem 2016 Aug 17;27(8):1911-20.PMID:27386732DOI:10.1021/acs.bioconjchem.6b00305.

We developed a hypoxia-inducible factor-1 (HIF-1) inhibitor, IDF-11774, as a clinical candidate for cancer therapy. To understand the mechanism of action of IDF-11774, we attempted to isolate target proteins of IDF-11774 using bioconjugated probes. Multifunctional chemical probes containing sites for click conjugation and photoaffinity labeling were designed and synthesized. After fluorescence and photoaffinity labeling of proteins, two-dimensional electrophoresis (2DE) was performed to isolate specific molecular targets of IDF-11774. Heat shock protein (HSP) 70 was identified as a target protein of IDF-11774. We revealed that IDF-11774 inhibited HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotide-binding domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate (OCR) and ATP production, thereby increasing intracellular oxygen tension. This result suggests that the inhibition of HSP70 chaperone activity by IDF-11774 suppresses HIF-1α refolding and stimulates HIF-1α degradation. Taken together, these findings indicate that IDF-11774-derived chemical probes successfully identified IDF-11774's target molecule, HSP70, and elucidated the mode of action of IDF-11774 in inhibiting HSP70 chaperone activity and stimulating HIF-1α degradation in cancer cells.

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth

Cell Death Dis 2017 Jun 1;8(6):e2843.PMID:28569777DOI:10.1038/cddis.2017.235.

HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

Br J Cancer 2018 Nov;119(11):1347-1357.PMID:30420612DOI:10.1038/s41416-018-0289-1.

Background: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation. Methods: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library. Results: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression. Conclusions: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.

Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro

Pharmaceuticals (Basel) 2020 Aug 24;13(9):208.PMID:32847004DOI:10.3390/ph13090208.

Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.