Defactinib hydrochloride
(Synonyms: VS-6063 hydrochloride; PF 04554878 hydrochloride) 目录号 : GC35827
Defactinib hydrochloride是一种小分子激酶抑制剂，可选择性抑制FAK和Pyk2。
Cas No.:1073160-26-5
Sample solution is provided at 25 µL, 10mM.
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Defactinib hydrochloride is a small molecule kinase inhibitor that selectively inhibits FAK and Pyk2 [1]. Defactinib hydrochloride inhibits FAK autophosphorylation (e.g., at Tyr397) and blocks integrin-mediated downstream RAS/MEK/ERK and PI3K/Akt signaling pathways, thereby inhibiting tumor cell proliferation, migration, survival, and angiogenesis [2-3]. Defactinib hydrochloride is commonly used to treat recurrent KRAS-mutant low-grade serous ovarian cancer [4].
In esophageal squamous cell carcinoma, Defactinib hydrochloride (0-25μM; 72h) significantly inhibited the growth of tumor cells [5]. In A549 cells, Defactinib hydrochloride (1μM; 48h) partially abolished G9a-enhanced invasion in cells [6].
In NCI-H358 cells xenograft tumor mice model, Defactinib hydrochloride (10mg/kg; ig; 28d) monotherapy inhibits tumor growth [7]. In A427 cells xenograft tumor mice model, Defactinib hydrochloride (10mg/kg; ip; 21d) inhibits tumor growth [8].
References:
[1]. Moore K, Walter A. Defactinib hydrochloride. Dual FAK1/PYK2 inhibitor, Treatment of non-small cell lung cancer, treatment of malignant mesothelioma, treatment of ovarian cancer[J]. Drugs of the Future, 2014, 39(11).
[2]. Ryzhakov G, Almuttaqi H, Corbin A L, et al. Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation[J]. Nature Communications, 2021, 12(1): 6702.
[3]. Riordan J D, Nathanson T A, Varzavand A, et al. A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition[J]. bioRxiv, 2024: 2024.12. 22.629990.
[4]. Banerjee S N. Avutometinib/Defactinib May be a New SOC in Low-Grade Serous Ovarian Cancer[J]. Cancer Network, 2023: NA-NA.
[5]. Zhang L, Zhao D, Wang Y, et al. Focal adhesion kinase (FAK) inhibitor‐defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network[J]. Molecular carcinogenesis, 2021, 60(2): 113-124.
[6]. Sun T, Zhang K, Pangeni R P, et al. G9a promotes invasion and metastasis of non–small cell lung cancer through enhancing focal adhesion kinase activation via NF-κB signaling pathway[J]. Molecular Cancer Research, 2021, 19(3): 429-440.
[7]. Yoshimura A, Horinaka M, Yaoi T, et al. Epithelial-mesenchymal transition status is a remarkable biomarker for the combination treatment with avutometinib and defactinib in KRAS-mutated non-small cell lung cancer[J]. British Journal of Cancer, 2024, 131(2): 361-371.
[8]. Liu J, Xue L, Xu X, et al. FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer[J]. Experimental Cell Research, 2021, 408(2): 112868.
Defactinib hydrochloride是一种小分子激酶抑制剂，可选择性抑制FAK和Pyk2 [1]。Defactinib hydrochloride可抑制FAK自身磷酸化（例如，在Tyr397位点），并阻断整合素介导的下游RAS/MEK/ERK和PI3K/Akt信号通路，从而抑制肿瘤细胞增殖、迁移、存活和血管生成 [2-3]。Defactinib hydrochloride常用于治疗复发性KRAS突变型低级别浆液性卵巢癌 [4]。
在食管鳞状细胞癌中，Defactinib hydrochloride（0-25μM；72h）显著抑制肿瘤细胞生长 [5]。在A549细胞中，Defactinib hydrochloride（1μM；48h）可部分消除G9a增强的细胞侵袭性 [6]。
在NCI-H358细胞异种移植瘤小鼠模型中，Defactinib hydrochloride（10mg/kg；ig；28d）单药治疗可抑制肿瘤生长 [7]。在A427细胞异种移植瘤小鼠模型中，Defactinib hydrochloride（10mg/kg；ip；21d）可抑制肿瘤生长 [8]。
| Cell experiment [1]: | |
Cell lines | Esophageal squamous cell carcinoma (ESCC) |
Preparation Method | The antiproliferative effect of Defactinib hydrochloride on ESCC cells was evaluated using 3‐(4, 5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐ (4‐sulfophenyl)‐2H‐tetrazolium, inner salt (MTS) method. Briefly, 3 × 103 indicated cells in 100μL of RPMI 1640 medium were seeded in 96‐well plates. Twenty‐four hours later, cells were attached and treated with different doses of Defactinib hydrochloride (0-25μM) for 72h. Then, the medium was discarded, and cells were incubated with MTS solution for 1h. Plates were scanned spectrophotometrically at 490nm, and the number of viable cells was positively correlated with the formazan product. |
Reaction Conditions | 0-25μM; 72h |
Applications | Defactinib hydrochloride significantly inhibited the growth of tumor cells. |
| Animal experiment [2]: | |
Animal models | NCI-H358 cells xenograft tumor mice model |
Preparation Method | A suspension of NCI-H358 cells (4 × 106 cells) was subcutaneously injected into the right flank of 6-week-old female BALB/c nu/nu mice and maintained under pathogen-free conditions. When tumors reached approximately 70-120mm in size, mice were randomly divided into four groups (n = 6 per group): 1) vehicle, 2) Defactinib hydrochloride (10mg/kg), 3) avutometinib (0.3mg/kg), and 4) avutometinib plus Defactinib hydrochloride. Avutometinib and Defactinib hydrochloride were dissolved in 20% hydroxypropyl-β-cyclodextrin/normal saline. Dosing was continued once daily by oral gavage until day 28, and the body weight and general condition of the mice were monitored daily. |
Dosage form | 10mg/kg; ig; 28d |
Applications | Defactinib hydrochloride monotherapy inhibits tumor growth. |
References: | |
| Cas No. | 1073160-26-5 | SDF | |
| 别名 | VS-6063 hydrochloride; PF 04554878 hydrochloride | ||
| Canonical SMILES | O=C(NC)C1=CC=C(NC2=NC=C(C(F)(F)F)C(NCC3=NC=CN=C3N(C)S(=O)(C)=O)=N2)C=C1.[H]Cl | ||
| 分子式 | C20H22ClF3N8O3S | 分子量 | 546.95 |
| 溶解度 | DMSO: 30 mg/mL (54.85 mM); Water: < 0.1 mg/mL (insoluble) | 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8283 mL | 9.1416 mL | 18.2832 mL |
| 5 mM | 0.3657 mL | 1.8283 mL | 3.6566 mL |
| 10 mM | 0.1828 mL | 0.9142 mL | 1.8283 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: >98.50%
- COA (Certificate Of Analysis)
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