Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. At higher concentrations, other tyrosine kinases are also inhibited, including PDGFR-β (IC₅₀ = 580 nM), c-KIT (IC₅₀ = 730 nM), FLT-4 (IC₅₀ = 660 nM) and c-FMS (IC₅₀ = 1.4 µM). On the other hand, vatalanib is not active against the EGFR, c-SRC, v-ABL, and protein kinase Cα (IC₅₀ > 10 µM). Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls. The inhibitor Vatalanib is possibly an additional option in the treatment of leiomyosarcomas.
|Preparation method||Endothelial Cell Proliferation Assays.
As a test of the ability of PTK787/ZK 222584 to inhibit a functional response to VEGF, an endothelial cell proliferation assay, based on BrdUrd incorporation was used (Biotrak Cell Proliferation System V.2, Amersham, England). Subconfluent HUVECs were seeded at a density of 5 3 103 cells/well into 96-well plates coated with 1.5% gelatin and then incubated at 37°C and 5% CO2 in growth medium. After 24 h, growth medium was replaced by basal medium containing 1.5% FCS and a constant concentration of VEGF (50 ng/ml), bFGF (0.5 ng/ml), or FCS (5%), in the presence or absence of PTK787/ZK 222584. As a control, wells without growth factor were also included. After 24 h of incubation, BrdUrd labeling solution was added, and cells incubated an additional 24 h before fixation, blocking, and addition of peroxidase-labeled anti-BrdUrd antibody. Bound antibody was then detected using 3,395,59-tetramethylbenzidine substrate, which results in a colored reaction product that is quantified spectrophotometrically at 450 nm.
|Incubation time||24 h|
|Animal models||Nude Mouse Human Tumor Xenograft Model|
|Dosages||25 to 100 mg/kg once or twice dail|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 25 mg/mL|
The inhibition of tyrosine kinase receptor signalling in leiomyosarcoma cells using the small molecule kinase inhibitor PTK787/ZK222584 (Vatalanib®).
Gaumann AK, et al. Int J Oncol. 2014 Dec;45(6):2267-77. PMID: 25340839.
Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001).
Dragovich T, et al. Cancer Chemother Pharmacol. 2014 Aug;74(2):379-87. PMID: 24939212.
Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance).
Wang X, et al. Br J Clin Pharmacol. 2014 Nov;78(5):1005-13. PMID: 24838014.
A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma.
Bitting RL, et al. Clin Genitourin Cancer. 2014 Aug;12(4):241-50. PMID: 24685058.
PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.
Wood JM, et al. Cancer Res. 2000 Apr 15;60(8):2178-89. PMID: 10786682.
|Related VEGFR/PDGFR Products|
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BAW2881 (NVP-BAW2881) is a potent and selective VEGFR2 inhibitor with activity to inhibit chronic and acute skin inflammation.
SU 1498 is a selective inhibitor of the receptor tyrosine kinase VEGF receptor 2 (VEGFR2, aka FLK1; IC50 = 700 nM).
Avitinib maleate is a pyrrolopyrimidine-based irreversible epidermal growth factor receptor (EGFR) inhibitor with an IC50 of 7.68 nM.
Fruquintinib (HMPL-013) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 33, 0.35, and 35 nM, respectively.
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