Derazantinib
(Synonyms: 德拉赞替尼,ARQ-087) 目录号 : GC19399
Derazantinib是一种新型的、ATP竞争性的小分子多激酶抑制剂，对FGFR2的 IC50 为 1.8nM，对FGFR1 和FGFR3的IC50 分别为4.5nM。
Cas No.:1234356-69-4
Sample solution is provided at 25 µL, 10mM.
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Derazantinib is a novel, ATP competitive, small molecule, multi-kinase inhibitor with IC50 of 1.8nM for FGFR2, and 4.5nM for FGFR1 and 3[1].
Derazantinib rescued the FGF2-mediated growth arrest with EC50 at ~100nM in rat chondrosarcoma (RCS) cells, with no significant toxicity detected for up to 500nM. The concentration range at which Derazantinib significantly suppressed the FGF2 effect was between 70-500nM. Derazantinib inhibits FGF-mediated loss of extracellular matrix and induction of chondrocyte premature senescence. Derazantinib reduced FGFR-driven excessive osteogenic differentiation in mouse mesenchymal micromass cultures and ex vivo calvarial organ cultures[2]. Derazantinib(100μM, 72h) has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between Derazantinib(1μM, 24h/72h) induced G1 cell cycle arrest and subsequent induction of apoptosis[1].
Derazantinib demonstrated efficacy in multiple in vivo xenograft models(NCI-H716 and SNU-16), and was well tolerated at doses up to 75mg/kg(administered orally, a single oral dose)[1]. Derazantinib is active and safe when administered daily for 10-15 days at a dose range of 50-150mg/kg given orally in xenograft models,which were obtained from H1581 lung cancer, MFE296 and SNU16 gastric cancer[3].
References:
[1] Hall T G, Yu Y, Eathiraj S, et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation[J]. PLoS One, 2016, 11(9): e0162594.
[2]Balek L, Gudernova I, Vesela I, et al. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3[J]. Bone, 2017, 105: 57-66.
[3]Chilà R, Hall T, Abbadessa G, et al. Multi-chemotherapeutic schedules containing the pan-FGFR inhibitor ARQ 087 are safe and show antitumor activity in different xenograft models[J]. Translational Oncology, 2017, 10(2): 153-157.
Derazantinib是一种新型的、ATP竞争性的小分子多激酶抑制剂，对FGFR2的 IC50 为 1.8nM，对FGFR1 和FGFR3的IC50 分别为4.5nM[1]。
Derazantinib可挽救大鼠软骨肉瘤（RCS）细胞中FGF2介导的生长停滞，其EC50约为100nM，在高达500nM的浓度下未检测到明显毒性。Derazantinib显著抑制FGF2效应的浓度范围在70-500nM之间。Derazantinib能抑制FGF介导的细胞外基质丢失和软骨细胞过早衰老。在小鼠间充质微团培养和离体颅骨器官培养中，Derazantinib可减少FGFR驱动的过度成骨分化[2]。Derazantinib（100μM，72小时）对由FGFR 失调（包括扩增、融合和突变）驱动的细胞系具有抗增殖活性。对FGFR2蛋白水平高的细胞系进行的细胞周期研究表明，Derazantinib（1μM，24小时/72小时）诱导的G1期细胞周期停滞与随后的凋亡诱导之间存在正相关[1]。
Derazantinib在多种体内异种移植模型（NCI-H716和SNU-16）中显示出疗效，并且在口服剂量高达75mg/kg（单次口服剂量）时耐受性良好[1]。在H1581肺癌、MFE296和SNU16胃癌的异种移植模型中，Derazantinib以50-150mg/kg的剂量口服给药，每日一次，持续10-15天时，具有活性且安全性良好[3]。
| Kinase experiment [1]: | |
Preparation Method | Derazantinib was first profiled against 298 kinases at a concentration of 0.1μM, kinases that inhibited greater than 50% at 0.1μM by ARQ-087 were subjected to IC50 determination. |
Reaction Conditions | 0.1μM |
Applications | Derazantinib appears to be most potent against FGFR1/2/3, however activity is also seen in a number of other kinases including RET, VEGFR, and KIT. |
| Cell experiment [1]: | |
Cell lines | NCI-H716, SNU-16, and KG-1. |
Preparation Method | Cells were seeded in 96-well tissue culture treated plates, incubated overnight and subsequently treated with 3-fold serial dilutions of Derazantinib starting at 100μM. The cells were returned to a 37°C humidified incubator for 72 hours. Cell Proliferation was detected by MTS assay. |
Reaction Conditions | 100μM; 72h |
Applications | Derazantinib has anti-proliferative activity in cell lines. |
| Animal experiment [1]: | |
Animal models | Female NCr nu/nu mice (SNU-16) or CB17 SCID mice (NCI-H716) |
Preparation Method | Female NCr nu/nu mice (SNU-16) or CB17 SCID mice (NCI-H716) with well established (~400 mg) subcutaneous tumors were given a single oral dose of ARQ-087 or vehicle control. Plasma and tumor samples were collected 4 hours post single dose. For all in vivo experiments, Derazantinib was formulated in DMA: cremophor EL: propylene glycol: 0.2M acetate buffer, pH 5 (10:10:30:50) and administered orally. Dosing volume for all groups was 10mL/kg or 0.1mL/10g body weight. |
Dosage form | 10mg/kg; single dose; p.o. |
Applications | Meaningful tumor inhibition was observed both cancer cell line derived xenograft models. |
References: | |
| Cas No. | 1234356-69-4 | SDF | |
| 别名 | 德拉赞替尼,ARQ-087 | ||
| Canonical SMILES | COCCNCCC1=CC(NC2=NC=C3C[C@@H](C4=CC=CC=C4F)C5=CC=CC=C5C3=N2)=CC=C1 | ||
| 分子式 | C29H29FN4O | 分子量 | 468.57 |
| 溶解度 | DMSO : ≥ 100 mg/mL (213.42 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 | 2.1342 mL | 10.6708 mL | 21.3415 mL |
| 5 mM | 0.4268 mL | 2.1342 mL | 4.2683 mL |
| 10 mM | 0.2134 mL | 1.0671 mL | 2.1342 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。
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet