Inecalcitol
(Synonyms: 伊奈骨化醇,TX 522) 目录号 : GC61948
Inecalcitol (TX 522) 是一种独特的维生素 D3 类似物，是一种具有口服活性维生素 D 受体 (VDR) 激动剂。Inecalcitol 可诱导细胞凋亡 (apoptosis)，并具有有效的抗癌活性。
Cas No.:163217-09-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Inecalcitol (TX 522), a unique vitamin D3 analog, is an orally active vitamin D receptor (VDR) agonist. Inecalcitol can induce cell apoptosis and has potent anticancer activities[1][2][3.
Inecalcitol (0.1-10 nM; 48 hours) treatment of LNCaP cells resulted in decreased expression of both protein and mRNA of Pim-1 in a dose-dependent manner. Inecalcitol (0.1-10 nM; 48 hours) also decreases ETV1 expression levels in a dose-dependent manner[1].Inecalcitol (10-14 days) inhibits the growth of LNCaP and HL-60 cells with ED50 values of 4.0 nM and 0.28 nM, respectively[1].
Inecalcitol (1.3 mg/kg; i.p.; 3 times per week; for 42 days) inhibits androgen-responsive prostate cancer growth in vivo[1]. Pharmacokinetic studies show that plasma half-life of Inecalcitol (C57Bl/6J mice; 1.3 mg/kg; i.p.) is 18.3 minutes in mice[1].
References:
[1]. Ryoko Okamoto, et al. Inecalcitol, an analog of 1α,25(OH)(2) D(3) , induces growth arrest of androgen-dependent prostate cancer cells. Int J Cancer. 2012 May 15;130(10):2464-73.
[2]. Jacques Medioni, et al. Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients. Clin Cancer Res. 2014 Sep 1;20(17):4471-7.
[3]. Yingyu Ma, et al. Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. Cell Cycle. 2013 Mar 1;12(5):743-52.
| Cas No. | 163217-09-2 | SDF | |
| 别名 | 伊奈骨化醇,TX 522 | ||
| Canonical SMILES | O[C@H]1C[C@H](O)C/C(C1)=C/C=C2[C@@]3([H])CC[C@H]([C@H](C)CC#CC(C)(O)C)[C@@]3(C)CCC/2 | ||
| 分子式 | C26H40O3 | 分子量 | 400.59 |
| 溶解度 | 储存条件 | 4°C, protect from light, 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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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4963 mL | 12.4816 mL | 24.9632 mL |
| 5 mM | 0.4993 mL | 2.4963 mL | 4.9926 mL |
| 10 mM | 0.2496 mL | 1.2482 mL | 2.4963 mL |
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动物平均体重 | g | |
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2.
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Inecalcitol, an analog of 1α,25(OH)(2) D(3) , induces growth arrest of androgen-dependent prostate cancer cells
Int J Cancer 2012 May 15;130(10):2464-73.PMID:21732345DOI:10.1002/ijc.26279.
19-nor-14-epi-23-yne-1,25(OH)(2) D(3) (Inecalcitol) is a unique vitamin D(3) analog. We evaluated the activity of Inecalcitol in a human prostate cancer model system. The analog was 11-fold more potent than 1,25(OH)(2) D(3) in causing 50% clonal growth inhibition of androgen-sensitive human prostate cancer LNCaP cells. Inecalcitol, more than 1,25(OH)(2) D(3) , reduced in a dose-dependent manner the expression levels of the transcription factor ETS variant 1 and the serine/threonine protein kinase Pim-1, both of which are upregulated in prostate cancer. Remarkably, dose challenge experiments revealed that Inecalcitol maximal tolerated dose (MTD) by intraperitoneal (i.p.) administration was 30 μg/mouse (1,300 μg/kg) three times per week, while we previously found that the MTD of 1,25(OH)(2) D(3) is 0.0625 μg/mouse; therefore, Inecalcitol is 480 times less hypercalcemic than 1,25(OH)(2) D(3) . Pharmacokinetic studies showed that plasma half-life of Inecalcitol were 18.3 min in mice. A xenograft model of LNCaP cells was developed in immunodeficient mice treated with Inecalcitol. The tumors of the diluent-treated control mice increased in size but those in the Inecalcitol treatment group did not grow. Our data suggest that Inecalcitol inhibits androgen-responsive prostate cancer growth in vivo and should be examined either alone or with other chemotherapy in clinical trials in individuals with rising serum prostate-specific antigen after receiving either surgery or irradiation therapy with curative intent.
Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system
Cell Cycle 2013 Mar 1;12(5):743-52.PMID:23388458DOI:10.4161/cc.23846.
Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, Inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of Inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, Inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC50 value 30 times lower than that of 1,25D₃. Both Inecalcitol and 1,25D₃ induced a comparable level of G0/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by Inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, Inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, Inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, Inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro Inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of Inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. Inecalcitol and attributed to the much shorter serum half-life of Inecalcitol.We show that Inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a strong induction of apoptosis. These findings support the further development of Inecalcitol in cancer treatment.
The Combination of the CDK4/6 Inhibitor, Palbociclib, With the Vitamin D3 Analog, Inecalcitol, Has Potent In Vitro and In Vivo Anticancer Effects in Hormone-Sensitive Breast Cancer, But Has a More Limited Effect in Triple-Negative Breast Cancer
Front Endocrinol (Lausanne) 2022 Jun 17;13:886238.PMID:35784555DOI:10.3389/fendo.2022.886238.
Active vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and its synthetically derived analogs possess potent anticancer properties. In breast cancer (BC) cells, 1,25(OH)2D3 blocks cell proliferation and induces apoptosis through different cell-type specific mechanisms. In this study, we evaluated if the combination of the potent vitamin D3 analog, Inecalcitol, with a selective CDK4/6 inhibitor, palbociclib, enhanced the antiproliferative effects of both single compounds in hormone-sensitive (ER+) BC, for which palbociclib treatment is already approved, but also in triple-negative BC (TNBC). Inecalcitol and palbociclib combination treatment decreased cell proliferation in both ER+ (T47D-MCF7) and TNBC (BT20-HCC1143-Hs578T) cells, with a more pronounced antiproliferative effect in the former. In ER+ BC cells, the combination therapy downregulated cell cycle regulatory proteins (p)-Rb and (p)-CDK2 and blocked G1-S phase transition of the cell cycle. Combination treatment upregulated p-mTOR and p-4E-BP1 protein expression in MCF7 cells, whereas it suppressed expression of these proteins in BT20 cells. Cell survival was decreased after Inecalcitol treatment either alone or combined in MCF7 cells. Interestingly, the combination therapy upregulated mitochondrial ROS and mitotracker staining in both cell lines. Furthermore, in vivo validation in a MCF7 cell line-derived xenograft mouse model decreased tumor growth and cell cycle progression after combination therapy, but not in a TNBC BT20 cell line-derived xenograft model. In conclusion, we show that addition of a potent vitamin D3 analog to selective CDK4/6 inhibitor treatment results in increased antiproliferative effects in ER+ BC both in vitro and in vivo.
Phase I safety and pharmacodynamic of Inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients
Clin Cancer Res 2014 Sep 1;20(17):4471-7.PMID:25013124DOI:10.1158/1078-0432.CCR-13-3247.
Purpose: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating Inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. Experimental design: Safety and efficacy were evaluated in groups of three to six patients receiving Inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. Results: Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of Inecalcitol. Calcemia normalized a few days after interruption of Inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. Conclusion: High antiproliferative daily Inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.
Vitamin D receptor as a target for breast cancer therapy
Endocr Relat Cancer 2017 Apr;24(4):181-195.PMID:28213567DOI:10.1530/ERC-16-0463.
Considerable epidemiological evidence suggests that high levels of circulating vitamin D (VD) are associated with a decreased incidence and increased survival from cancer, i.e., VD may possess anti-cancer properties. The aim of this investigation was therefore to investigate the anti-cancer potential of a low calcaemic vitamin D analogue, i.e., Inecalcitol and compare it with the active form of vitamin D, i.e., calcitriol, in a panel of breast cancer cell lines (n = 15). Using the MTT assay, IC50 concentrations for response to calcitriol varied from 0.12 µM to >20 µM, whereas those for Inecalcitol were significantly lower, ranging from 2.5 nM to 63 nM (P = 0.001). Sensitivity to calcitriol and Inecalcitol was higher in VD receptor (VDR)-positive compared to VDR-negative cell lines (P = 0.0007 and 0.0080, respectively) and in ER-positive compared to ER-negative cell lines (P = 0.043 and 0.005, respectively). Using RNA-seq analysis, substantial but not complete overlap was found between genes differentially regulated by calcitriol and Inecalcitol. In particular, significantly enriched gene ontology terms such as cell surface signalling and cell communication were found after treatment with Inecalcitol but not with calcitriol. In contrast, ossification and bone morphogenesis were found significantly enriched after treatment with calcitriol but not with Inecalcitol. Our preclinical results suggest that calcitriol and Inecalcitol can inhibit breast cancer cell line growth, especially in cells expressing ER and VDR. As Inecalcitol is significantly more potent than calcitriol and has low calcaemic potential, it should be further investigated for the treatment of breast cancer.