Vascular endothelial growth factor tyrosine kinase inhibitors

Goss G et al (2009) A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer a study of the national cancer institute of Canada clinical trials group. Eur J Cancer 45 782-788... 

D. Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitors... 

Optimization of the large (MW = 512), lipophilic (clogP = 7.6), and very potent (Kj = 0.22 nM) Vascular Endothelial Growth Factor Receptor Tyrosine Kinase (VEGFR TK) inhibitor 8 (LLE = 2.1) to produce the development candidate axitinib (9) was recently reported [17]. 

B.K., Yu, S. and Hartman, G.D. (2004) Potent N-(l,3-thiazoyl-2-yl)pyridine-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel. Journal of Medicinal Chemistry, 47, 6363-6372. 

Schlaeppi JM, Wood JM. Targeting vascular endothelial growth factor (VEGF) for anti-tumor therapy, by anti-VEGF neutralizing monoclonal antibodies or by VEGF receptor tyrosine kinase inhibitors. Cancer Metastasis Rev 1999 18 4734-81. 

Fong TAT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-l/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999 59 99-106. 

S. K. Kelley, and A. Sandler. 2005. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-l/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer./. Clin. Oncol. 23 2544-2555. 

Mendel DB et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9 327-337... 

Reardon DA et al (2009) Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 115 2188-2198... 

Wood, J. M., Bold, G., Buchdunger, E., Cozens, R., Ferrari, S., et al. 2000. 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. Cancer Res. 60 2178-2189. 

The key to expanding a stem cell population is to understand the requirements for proliferation without inducing differentiation. In the case of self-renewal some elements seem to be essential. Examples are the homeotic gene HOXB4, the cytokines FLT-3L (fms-related tyrosine kinase ligand), LIF (leukemia inhibitor factor), interleukin (IL)-3, VEGF (vascular endothelial growth factor), and proteins of the WNT and... 

Figure 4.10 Example of a heterogeneous SAR. Four inhibitors of vascular endothelial growth factor receptor (YEGFR-2) tyrosine kinase are shown. The two inhibitors at the top have different core structures but equally high potency and are thus part of a continuous SAR. By contrast, closely related analogs of each inhibitor shown at the bottom have several orders of magnitude lower potency, which is a characteristic feature of discontinuous SARs.

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