CUDC-427 (GDC-0917)
(Synonyms: GDC-0917) 目录号 : GC32781
CUDC-427 (GDC-0917) 是一种有效的第二代泛选择性 IAP 拮抗剂，用于治疗各种癌症。
Cas No.:1446182-94-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Animal experiment: |
Briefly, 10 million MDA-MB-231-X1.1 breast adenocarcinoma cells resuspended in Hank’s balanced salt solution and Matrigel (1:1, v/v) are implanted subcutaneously into the upper right flank of female SCID.bg mice. MDA-MB-231-X1.1 cells are MDA-MB-231 cells that are selected for improved in vivo growth rates. When tumor volumes reach approximately 100-300 mm3, mice are assigned to treatment groups to get a similar mean tumor size for each treatment group. Treatment groups (n=5 per group) are administered once daily oral doses of vehicle (15% hydroxypropyl-β-cyclodextrin, 20 mM succinic acid in water), 0.08, 0.17, 0.34, 0.68, 1.36, 2.72, 5.43, 10.87, or 16.30 mg/kg of GDC-0917 for 21 days. Tumor volumes are measured in two dimensions (length and width) using Ultra Cal IV calipers. Tumor sizes and body weights are recorded twice weekly, and the mice are regularly observed over the course of the study. Mice are euthanized if their tumor volume exceeds 2000 mm3 or if their body weight drops by more than 20% of the starting weight. |
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References: [1]. Wong H, et al. Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist. Drug Metab Dispos. 2013 Dec;41(12):2104-13. |
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CUDC-427 is a potent second-generation pan-selective IAP antagonist, used for treatment of various cancers.
GDC-0917 (0.1 nM-10 μM) induces reduction of cIAP1 levels in PBMCs in a concentration-dependent manner showing greater than 80% inhibition at concentrations greater than 0.1 µM (56.5 ng/mL)[1].
GDC-0917 (0.08-16.3 mg/kg) exhibits antitumor activity in a dose dependent manner in the MDA-MB-231-X1.1 Breast Cancer Xenograft, and GDC-0917 is well tolerated, with all dose groups experiencing a <11% decrease in mean body weight. GDC-0917 has low to moderate clearance in the mouse (12.0 mL/min/kg), rat (27.0 mL/min/kg), and dog (15.3 mL/min/kg), and high clearance in the monkey (67.6 mL/min/kg). Oral bioavailability is lowest in monkeys compared with other species[1].
[1]. Wong H, et al. Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist. Drug Metab Dispos. 2013 Dec;41(12):2104-13.
| Cas No. | 1446182-94-0 | SDF | |
| 别名 | GDC-0917 | ||
| Canonical SMILES | O=C([C@H](CCC1)N1C([C@H](C2CCCCC2)NC([C@H](C)NC)=O)=O)NC3=C(C4=CC=CC=C4)N=C(C5=NC=CO5)S3 | ||
| 分子式 | C29H36N6O4S | 分子量 | 564.7 |
| 溶解度 | DMSO : ≥ 61 mg/mL (108.02 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 | 1.7709 mL | 8.8543 mL | 17.7085 mL |
| 5 mM | 0.3542 mL | 1.7709 mL | 3.5417 mL |
| 10 mM | 0.1771 mL | 0.8854 mL | 1.7709 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。
A Phase I Dose-Escalation Study Evaluating the Safety Tolerability and Pharmacokinetics of CUDC-427, a Potent, Oral, Monovalent IAP Antagonist, in Patients with Refractory Solid Tumors
Clin Cancer Res 2016 Sep 15;22(18):4567-73.PMID:27076626DOI:10.1158/1078-0432.CCR-16-0308
Purpose: To determine the dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins. Experimental design: Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily 14-day on/7-day off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMC), and monocyte chemoattractant protein-1 (MCP-1) levels. Results: Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1, and 5 patients experienced AEs related to CUDC-427 that led to discontinuation and included grade 3 pruritus, and fatigue, and grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg orally daily for 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses in one patient with ovarian cancer and one patient with MALT lymphoma. Conclusions: CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies. Clin Cancer Res; 22(18); 4567-73. ©2016 AACR.