Sitravatinib是一种酪氨酸激酶抑制剂（TKI），能够作用于TYRO3、AX和MERTK（TAM）受体、血管内皮生长因子受体（VEGFR）家族、c-Kit 和 c-MET。
Cas No.:1123837-84-2
Sample solution is provided at 25 µL, 10mM.
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Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets the TYRO3, AXL, and MERTK (TAM) receptors, the vascular endothelial growth factor receptor (VEGFR) family, c-Kit, and c-MET[1,2].
In vitro，Sitravatinib treatment decreased MET, EphA2, EphA3, or AXL protein phosphorylation levels in sunitinib and axitinib-resistant (SuR/AxR) human LM2-4 and mouse RENCA or 4T1 cells after 3 hours, enhanced effect in resistant cell lines[2]. The IC50 values for the three sensitive cell lines (DDLS, MPNST and LS141) ranged between 250–750nM, IC50 values for the less sensitive cell lines (A673 and Saos2) ranged between 1.5–2.0mM[3].
In vivo, Sitravatinib (2mg/kg; oral; every other day for 14 days) alone had 37% inhibitory effect on tumor volume (IRV) and 28% inhibitory effect on tumor weight (IRW) in the SW620 mice[4]. Sitravatinib (p.o.; 20mg/kg; once per day for 24 days) significantly inhibited tumor progression and induced tumor regression in immunocompetent mice bearing KLN205, CT1B-A5, or E0771 tumors[5].
References:
[1] Msaouel, Pavlos, et al. "Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial." Nature communications 16.1 (2025): 578.
[2] Dolan, Melissa, et al. "Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance." PloS one 14.8 (2019): e0220101.
[3] Patwardhan, Parag P., et al. "Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma." Oncotarget 7.4 (2015): 4093.
[4] Yang, Yuqi, et al. "Modulating the function of ABCB1: in vitro and in vivo characterization of sitravatinib, a tyrosine kinase inhibitor." Cancer Communications 40.7 (2020): 285-300.
[5] Du, Wenting, et al. "Sitravatinib potentiates immune checkpoint blockade in refractory cancer models." JCI insight 3.21 (2018): e124184.
Sitravatinib是一种酪氨酸激酶抑制剂（TKI），能够作用于TYRO3、AX和MERTK（TAM）受体、血管内皮生长因子受体（VEGFR）家族、c-Kit 和 c-MET[1,2]。
在体外实验中，Sitravatinib治疗在3小时后降低了sunitinib和sunitinib耐药（SuR/AxR）的人类 LM2-4 和小鼠 RENCA 或 4T1 细胞中的 MET、EphA2、EphA3或AXL蛋白的磷酸化水平，且在耐药细胞系中的效果更显著[2]。三种敏感细胞系（DDLS、MPNST和LS141）的IC50值250–750nM之间，而不太敏感的细胞系（A673和Saos2）的IC50值在1.5–2.0mM之间[3]。
在体内实验中，单独使用Sitravatinib（2mg/kg；口服；每隔一天一次，持续14天）对SW620小鼠的肿瘤体积抑制率为37%，对肿瘤重量抑制率为28%[4]。Sitravatinib（口服；20mg/kg；每天一次；24天）显著抑制了携带KLN205、CT1B-A5或E0771肿瘤的免疫功能正常的小鼠的肿瘤进展，并诱导肿瘤消退[5]。
| Cell experiment [1]: | |
Cell lines | Sunitinib and axitinib-resistant (SuR/AxR) human LM2-4 and mouse RENCA or 4T1 cells |
Preparation Method | 5x103 and 1x103 cells/well (for human and mouse SuR/AxR cell lines, respectively) were plated in 96-well plates in growth media. The next day, growth media was removed and replaced with media containing various concentrations of sitravatinib or cabozantinib. Sitravatinib concentrations ranged between 1 and 10μM for human and 0.02 and 10μM for mouse cell lines, and cabozantinib concentrations ranged between 0.01 and 10μM for mouse cell lines. Preliminary studies were conducted using multiple concentration ranges to arrive at optimal concentrations for IC50 determination. After 72 hours, MTS was added to the cells and, after 2 hours, measured at a wavelength of 490nm using a spectrophotometer. |
Reaction Conditions | 1 and 10μM for human and 0.02 and 10μM for mouse cell lines; 72 hours |
Applications | Sitravatinib drug concentrations needed to reach 50% inhibition (IC50) was consistently less in SuR/AxR cells. |
| Animal experiment [2]: | |
Animal models | SW620 and SW620/Ad300 cells transplanted nude mice |
Preparation Method | SW620 and SW620/Ad300 cells were harvested and washed twice with PBS. Then, both cell lines (1×107 cells in 0.1mL PBS) were injected subcutaneously under armpits of the nude mice. Once the tumor volume reached 500mm3, the mice were euthanized, and the tumor tissues were dissected. Each tumor tissue, except the necrotic part, was cut into 2×2mm in size. The small tumor pieces were implanted subcutaneously under armpits of the nude mice. When the tumor reached approximately 100mm3, the mice were randomly assigned to the following four groups. Sitravatinib was prepared in a final concentration of 0.5% hydroxypropyl methylcellulose (HPMC) and 0.1% Tween-80 solution (pH 1.4) (vehicle A), while vincristine was prepared in autoclaved water (vehicle B). Group 1 mice received vehicle A (administered orally) 1h prior to vehicle B (administered intraperitoneally). Group 2 mice received sitravatinib (prepared in vehicle A, 2mg/kg, administered orally) 1h prior to vehicle B (administered intraperitoneally). Group 3 mice received vehicle A (administered orally) 1h prior to vincristine (prepared in vehicle B, 0.4mg/kg, administered intraperitoneally). Group 4 mice received sitravatinib 1h prior to vincristine at indicated dosages. All treatments were given every other day for 14 days. |
Dosage form | 2mg/kg; oral; every other day for 14 days. |
Applications | Sitravatinib alone had 37% inhibitory effect on tumor volume (IRV) and 28% inhibitory effect on tumor weight (IRW) compared with the control group treated with vehicle only in the SW620 mice. The growth of xenograft tumors was significantly inhibited by combination of sitravatinib and vincristine with 76% IRV and 89% IRW. |
References: | |
| Cas No. | 1123837-84-2 | SDF | |
| 别名 | MGCD516; MG-516 | ||
| Canonical SMILES | O=C(C1(C(NC2=CC=C(F)C=C2)=O)CC1)NC3=CC=C(OC4=C5C(C=C(C6=NC=C(CNCCOC)C=C6)S5)=NC=C4)C(F)=C3 | ||
| 分子式 | C33H29F2N5O4S | 分子量 | 629.68 |
| 溶解度 | DMSO : ≥ 32 mg/mL (50.82 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 | 1.5881 mL | 7.9405 mL | 15.8811 mL |
| 5 mM | 317.6 μL | 1.5881 mL | 3.1762 mL |
| 10 mM | 158.8 μL | 794.1 μL | 1.5881 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。
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