Cabozantinib S-malate (XL184) is the s-malate salt form of cabozantinib, an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity.

c-Met:1.3 nM, VEGFR2/KDR:0.035 nM

Cabozantinib 对RON和PDGFRβ展现出弱抑制活性，分别具有124 nM和234 nM的IC50值，对FGFR1的抑制活性较低，IC50值为5.294 μM。[1]低浓度Cabozantinib（0.1-0.5 μM）足以显著抑制MPNST细胞中Met磷酸化的常态和可诱导性，及其随后的下游信号传导，并阻止HGF诱导的MPNST细胞迁移与侵入。Cabozantinib还明显抑制了细胞因子刺激的人脐静脉内皮细胞（HUVECs）中Met和VEGFR2的磷酸化。尽管Cabozantinib在0.1 μM浓度下对MPNST细胞生长无显著影响，但在5-10 μM浓度时显著抑制MPNST细胞生长。[2]

Cabozantinib以30 mg/kg剂量在具有自发性胰岛肿瘤的RIP-Tag2小鼠治疗中，能破坏83%的肿瘤血管结构，减少周细胞和空的基底膜套管，导致广泛的肿瘤内缺氧和大量肿瘤细胞凋亡，并且在停药后减缓肿瘤血管再生速度。与仅阻断VEGFR而不影响c-Met的XL999相比，显著性地更强，后者仅导致血管减少43%，这表明同时抑制VEGFR及其他功能相关的受体酪氨酸激酶(RTK)能够加强抗血管生成作用。Cabozantinib还降低了原发肿瘤的侵袭性和转移。[1] Cabozantinib每天30 mg/kg剂量显著抑制人MPNST异种移植瘤在SCID小鼠中的生长和转移。[2] Cabozantinib的给药能在乳腺、肺和胶质瘤模型中引起剂量依赖性的肿瘤生长抑制，与此相关的是减少了肿瘤及内皮细胞的增殖和增加了凋亡。在MDA-MB-231瘤小鼠和C6瘤大鼠中，单次口服Cabozantinib以100 mg/kg和10 mg/kg的剂量即可持续抑制肿瘤生长。[3]

The inhibition profile of cabozantinib against a broad panel of 270 human kinases is determined using luciferase-coupled chemiluminescence,?33P-phosphoryl transfer, or AlphaScreen technology. Recombinant human full-length, glutathione?S-transferase tag, or histidine tag fusion proteins are used, and half maximal inhibitory concentration (IC50) values are determined by measuring phosphorylation of peptide substrate poly (Glu, Tyr) at ATP concentrations at or below the?Km?for each respective kinase. The mechanism of kinase inhibition is evaluated using the AlphaScreen Assay by determining the IC50?values over a range of ATP concentrations.

Cells are exposed to various concentrations of Cabozantinib for 48 hours. Cell growth is determined by MTS assays using CellTiter96 Aqueous Non-Radioactive Cell Proliferation Assay kit. Absorbance is measured at a wavelength of 490 nm, and the absorbance values of treated cells are presented as a percentage of the absorbance of untreated cells. (Only for Reference)