VEGFR2/KDR (IC50 = 0.035 nM); c-Met (IC50 = 1.3 nM); RET (IC50 = 4 nM); Kit (IC50 = 4.6 nM); Flt-4 (IC50 = 6 nM)

体外活性：XL184对RON和PDGFRβ具有弱抑制活性，IC50分别为124 nM和234 nM，对FGFR1具有低活性，IC50为5.294 μM。低浓度（0.1-0.5 μM）的 XL184 足以显着抑制 MPNST 细胞中的组成型和诱导型 Met 磷酸化及其由此产生的下游信号传导，并抑制 HGF 诱导的 MPNST 细胞迁移和侵袭。 XL184 还可显着抑制细胞因子刺激的人脐静脉内皮细胞 (HUVEC) 中的 Met 和 VEGFR2 磷酸化。虽然 0.1 μM 的 XL-184 对 MPNST 细胞的生长没有显着影响，但 5-10 μM 的 XL184 显着抑制 MPNST 细胞的生长。激酶测定：Cabozantinib (XL184, BMS-907351) 是一种有效的 VEGFR2 抑制剂，IC50 为 0.035 nM，还抑制 c-Met、Ret、Kit、Flt-1/3/4、Tie2 和 AXL，IC50 为 1.3 nM，分别为 4 nM、4.6 nM、12 nM/11.3 nM/6 nM、14.3 nM 和 7 nM。细胞测定：将细胞（ST88-14、STS26T 和 MPNST724）暴露于不同浓度的 XL184 中 48 小时。使用 CellTiter96 水性非放射性细胞增殖测定试剂盒通过 MTS 测定测定细胞生长。在 490 nm 波长处测量吸光度，处理细胞的吸光度值以未处理细胞吸光度的百分比表示。

对患有自发性胰岛肿瘤的 RIP-Tag2 小鼠进行 30 mg/kg XL184 治疗会破坏 83% 的肿瘤脉管系统，减少周细胞和空基膜套，导致广泛的瘤内缺氧和广泛的肿瘤细胞凋亡，并减缓肿瘤脉管系统的再生停药后，与阻断 VEGFR 但不阻断 c-Met 的 XL999 相比，效果更显着，导致血管分布仅减少 43%，表明同时抑制 VEGFR 和其他功能相关受体酪氨酸激酶 (RTK) 会放大血管生成抑制。 XL184 还可以降低原发肿瘤的侵袭性并减少转移。 30 mg/kg/天的 XL184 可显着消除 SCID 小鼠中的人类 MPNST 异种移植物的生长和转移。 XL184 的给药可诱导乳腺、肺和神经胶质瘤模型中肿瘤生长的剂量依赖性抑制，与肿瘤和内皮细胞增殖减少以及细胞凋亡增加相关。单次口服剂量的 XL184 足以分别以 100 mg/kg 和 10 mg/kg 剂量诱导 MDA-MB-231 荷瘤小鼠和 C6 荷瘤大鼠持续抑制肿瘤生长。

作为 VEGFR2 的强抑制剂，卡博替尼 (XL184, BMS-907351) 的 IC50 为 0.035 nM。对于 c-Met、Ret、Kit、Flt-1/3/4、Tie2 和 AXL，其 IC50 分别为 1.3 nM、4 nM、4.6 nM、12 nM/11.3 nM/6 nM、14.3 nM 和 7 nM ， 分别。

将细胞暴露于不同剂量的卡博替尼 48 小时。使用 CellTiter96 水性非放射性细胞增殖检测试剂盒，MTS 检测可用于测量细胞生长。测量吸光度的波长为 490 nm，处理细胞的吸光度值表示为未处理细胞吸光度的百分比。

RIP-Tag2 transgenic mice in a C57BL/6 background with spontaneous pancreatic islet tumors
~60 mg/kg
Oral gavage

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of cabozantinib during breastfeeding. Because cabozantinib is more than 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life ranges from 55 to 99 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during cabozantinib therapy and for 4 months after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res, 2011, 71(14), 4758-4768.

[2]. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res, 2011, 17(12), 3943-3955.

[3]. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther, 2011, 10(12), 2298-2308.

Cabozantinib malate is a malate salt that is the mono-(S)-malate salt of cabozantinib. A multi-tyrosine kinase inhibitor, used for the treatment of progressive, metastatic, medullary thyroid cancer. It has a role as a tyrosine kinase inhibitor, an antineoplastic agent and a prodrug. It contains a cabozantinib.
Cabozantinib S-malate is the s-malate salt form of cabozantinib, an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis, and eventually lead to tumor regression.
See also: Cabozantinib (has active moiety).

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Drug Indication
Treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma.
Renal Cell Carcinoma (RCC)Cabometyx is indicated as monotherapy for the treatment of advanced renal cell carcinoma (RCC): in treatment-naïve adults with intermediate or poor risk,in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. Cabometyx, in combination with nivolumab, is indicated for the first-line treatment of advanced renal cell carcinoma in adults. Hepatocellular Carcinoma (HCC)Cabometyx is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.

C32H30FN3O10

635.59

635.191

C, 60.47; H, 4.76; F, 2.99; N, 6.61; O, 25.17

1140909-48-3

Cabozantinib;849217-68-1

25102846

White to off-white solid powder

4.593

193.61

5

12

11

46

924

1

O=C([C@H](CC(O)=O)O)O.O=C(NC1=CC=C(C=C1)OC2=CC=NC3=CC(OC)=C(C=C23)OC)C4(CC4)C(NC5=CC=C(C=C5)F)=O

HFCFMRYTXDINDK-WNQIDUERSA-N

InChI=1S/C28H24FN3O5.C4H6O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18;5-2(4(8)9)1-3(6)7/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34);2,5H,1H2,(H,6,7)(H,8,9)/t;2-/m.0/s1

1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;(2S)-2-hydroxybutanedioic acid

Cabozantinib malate; XL-184; BMS-907351; XL184; XL 184; BMS907351; BMS 907351; Cabozantinib S-malate. Brand name: Cometriq

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)