Carboxyamidotriazole Orotate
(Synonyms: L-651582 Orotate; CAI Orotate) 目录号 : GC39646
A non-selective calcium channel blocker
Cas No.:187739-60-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Carboxyamidotriazole is an orally bioavailable, non-selective calcium channel blocker.1 It blocks L- and T-type calcium channels in GH3 rat pituitary cancer cells (IC50s = 0.5 and 1.5 μg/ml, respectively). It also inhibits calcium influx stimulated by the acetylcholine receptor agonist carbachol and the calcium ionophore A23187 in CHO cells expressing human recombinant muscarinic M5 receptors (IC50s = 935 and 359 nM, respectively).2 Carboxyamidotriazole inhibits the growth of T. gondii in non-cancerous human fibroblasts and HeLa human cervical cancer cells (IC50 = 0.06 μg/ml for both).3 It inhibits the growth of FaDu and EVSCC17M human squamous cell carcinoma cells (IC50s = 13 and 15 μM, respectively) and of human umbilical vein endothelial cells (HUVECs; IC50 = 1 μM) in vitro.4,5 Carboxyamidotriazole (20 μM) also inhibits angiogenesis in a chicken chorioallantoic membrane assay in vivo.5
1.Hupe, D.J., Boltz, R., Cohen, C.J., et al.The inhibition of receptor-mediated and voltage-dependent calcium entry by the antiproliferative L-651,582J. Biol. Chem.266(16)10136-10142(1991) 2.Felder, C.C., Ma, A.L., Liotta, L.A., et al.The antiproliferative and antimetastatic compound L651582 inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid releaseJ. Pharmacol. Exp. Ther.257(3)967-971(1991) 3.Hupe, D.J., Pfefferkorn, E.R., Behrens, N.D., et al.L-651,582 inhibition of intracellular parasitic protozoal growth correlates with host-cell directed effectsJ. Pharmacol. Exp. Ther.256(2)462-467(1991) 4.Wu, Y., Palad, A.J., Wasilenko, W.J., et al.Inhibition of head and neck squamous cell carcinoma growth and invasion by the calcium influx inhibitor carboxyamido-triazoleClin. Cancer Res.3(11)1915-1921(1997) 5.Kohn, E.C., Alessandro, R., Spoonster, J., et al.Angiogenesis: Role of calcium-mediated signal transductionProc. Natl. Acad. Sci. USA92(5)1307-1311(1995)
| Cas No. | 187739-60-2 | SDF | |
| 别名 | L-651582 Orotate; CAI Orotate | ||
| Canonical SMILES | O=C(C(NC1=O)=CC(N1)=O)O.O=C(C2=C(N)N(CC3=CC(Cl)=C(C(C4=CC=C(Cl)C=C4)=O)C(Cl)=C3)N=N2)N | ||
| 分子式 | C22H16Cl3N7O6 | 分子量 | 580.76 |
| 溶解度 | DMSO: 5 mg/mL (8.61 mM) | 储存条件 | Store at -20°C |
| 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 | 1.7219 mL | 8.6094 mL | 17.2188 mL |
| 5 mM | 0.3444 mL | 1.7219 mL | 3.4438 mL |
| 10 mM | 0.1722 mL | 0.8609 mL | 1.7219 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas
J Clin Oncol 2018 Jun 10;36(17):1702-1709.PMID:29683790DOI:10.1200/JCO.2017.76.9992.
Purpose Carboxyamidotriazole Orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.