Cabozantinib是一种酪氨酸激酶抑制剂， 抑制多受体VEGFR2、c-Met、Kit、Axl和FLT3的IC50分别为0.035、1.3、4.6、7 和 11.3 nM。

Cabozantinib (XL184) is a potent pan-tyrosine kinases inhibitor that inhibits VEGFR2, c-Met, Kit, Axl, and Flt3 (IC50s: 0.035, 1.3, 4.6, 7 and 11.3 nM).

Cabozantinib (XL184) is a potent inhibitor of MET and VEGFR2 (IC50s: 1.3 and 0.035 nmol/L). MET-activating kinase domain mutations Y1248H, D1246N or K1262R were also inhibited by cabozantinib (IC50s: 3.8, 11.8, and 14.6 nmol/L). Cabozantinib displayed strong inhibition of several kinases that have also been implicated in tumor pathobiology, including KIT, RET, AXL, TIE2, and FLT3 (IC50s: 4.6, 5.2, 7, 14.3, and 11.3 nmol/L). In cellular assays, cabozantinib inhibited phosphorylation of MET and VEGFR2, as well as KIT, FLT3, and AXL (IC50s: 7.8, 1.9, 5.0, 7.5, and 42 μmol/L). Cabozantinib inhibited tubule formation (IC50: 6.7 nmol/L) with no evidence of cytotoxicity. Cabozantinib also inhibited tubule formation in response to conditioned media derived from cultures of MDA-MB-231 (IC50: 5.1 nmol/L), A431 (IC50: 4.1 nmol/L), HT1080 (IC50: 7.7 nmol/L), and B16F10 (IC50: 4.7 nmol/L) cells [1]. Only minimal impact on growth was seen with low XL184 doses (0.1μM/48h). However, increased XL184 doses did elicit a significant MPNST cell growth inhibition; higher XL184 doses were needed to inhibit NSC growth [2].

A single 100 mg/kg oral dose of cabozantinib resulted in inhibition of phosphorylation of MET 2 to 8 hours postdose in H441 tumors that harbor constitutively phosphorylated MET. In separate experiments, cabozantinib inhibited in vivo stimulation of MET phosphorylation by HGF in liver hepatocytes and VEGF-stimulated phosphorylation of FLK1 with inhibition of both targets sustained through 8 hours postdose [1]. XL184 (30mg/kg/d, p.o.) treated tumors exhibited significantly slower growth. Moreover, treatment with XL184 significantly reduced tumor size and weight compared to control; average tumor weights at study termination were 0.84 g and 0.11 g in control and XL184 groups, respectively [2]. Cabozantinib (60 mg/kg per os daily) inhibited tumor growth based on BLI. Cabozantinib decreased the Ace1luc-induced osteoblastic lesions based on both radiographs and micro CT and a decrease of BMC towards the normal baseline [3].

The inhibition profile of cabozantinib against a broad panel of 270 human kinases was determined using luciferase-coupled chemiluminescence, 33P-phosphoryl transfer, or AlphaScreen technology. Recombinant human full-length, glutathione S-transferase tag or histidine tag fusion proteins were used, and half maximal inhibitory concentration (IC50) values were 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 was evaluated using the AlphaScreen Assay by determining the IC50 values over a range of ATP concentrations [1].

Receptor phosphorylation of MET, VEGFR2, AXL, FLT3, and KIT were, respectively, assessed in PC3, HUVEC, MDA-MB-231, FLT3-transfected BaF3, and KIT-transfected MDA-MB-231 cells. Cells were serum starved for 3 to 24 hours, then incubated for 1 to 3 hours in serum-free medium with serially diluted cabozantinib before 10-minute stimulation with ligand: HGF (100 ng/mL), VEGF (20 ng/mL), SCF (100 ng/mL), or ANG1 (300 ng/mL). Receptor phosphorylation was determined either by ELISA using specific capture antibodies and quantitation of total phosphotyrosine or immunoprecipitation and Western blotting with specific antibodies and quantitation of total phosphotyrosine. Total protein served as loading controls [1].

Female nu/nu mice were housed according to the Exelixis Institutional Animal Care and Use Committee guidelines. H441 cells (3 × 10^6) were implanted intradermally into the hind flank and when tumors reached approximately 150 mg, tumor weight was calculated using the formula: (tumor volume = length (mm) × width^2 (mm^2)]/2, mice were randomized (n = 5 per group) and orally administered a single 100 mg/kg dose of cabozantinib or vehicle. Tumors were collected at the indicated time points. Pooled tumor lysates were subjected to immunoprecipitation with anti-MET and Western blotting with anti-phosphotyrosine MET. After blot stripping, total MET was quantitated as a loading control. In a separate experiment, naive mice (n = 5 per group) were administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of HGF (10 μg per mouse) 10 minutes before liver collection. Analysis of MET phosphorylation in liver lysates was as described above. In a separate experiment, naive mice (n = 5 per group) were administered a single 100 mg/kg dose of cabozantinib or vehicle, followed by intravenous administration of VEGF (10 μg per mouse) 30 minutes before lung collection. Pooled lung lysates were subjected to immunoprecipitation with FLK1 and Western blotting with anti-phosphotyrosine. After blot stripping, total FLK1 was quantitated as a loading control [1].

849217-68-1

C28H24FN3O5

501.514

BMS-907351;XL184;卡博替尼

H2O:<1 mgml
DMSO:93 mg/mL (185.4 mM)
Ethanol:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years