Tie2/VEGFR2 Kinase-IN-2

Tie2/VEGFR2 kinase-IN-2 is an inhibitor of tunica interna endothelial cell kinase 2 (Tie2) and VEGFR2 (IC₅₀s = 13.49 and 7.76 nM, respectively).¹ It is selective for Tie2 and VEGFR2 over Akt3, cyclin-dependent kinase 2 (Cdk2), EGFR, and glycogen synthase kinase 3 (GSK3; IC₅₀s = >10,000, >10,000, 10,000, and 2,187 nM, respectively) but does inhibit VEGFR1 and VEGFR3 (IC₅₀s = 8.51 and 7.59 nM, respectively). Tie2/VEGFR2 kinase-IN-2 inhibits VEGF-induced increases in the proliferation of human umbilical vein endothelial cells (HUVECs) and GM-CSF-induced increases in Tie2 autophosphorylation in NIH3T3 fibroblasts expressing chimeric CSF-1 receptor tyrosine kinase (FMS) and Tie2 receptors (IC₅₀s = 2.6 and 18.3 nM, respectively). It reduces tumor volume and intratumoral vessel density in an HT-29 colon cancer mouse xenograft model when administered at doses of 3, 10, or 30 mg/kg per day. Tie2/VEGFR2 kinase-IN-2 (20 mg/kg) prevents decreases in body temperature in a mouse model of Tnf-α-induced lethal shock.²

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1. Miyazaki, Y., Tang, J., Maeda, Y., et al. Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2. Bioorg. Med. Chem. Lett. 17(6), 1773-1778 (2007).

2. Harris, P.A., Bandyopadhyay, D., Berger, S.B., et al. Discovery of small molecule RIP1 kinase inhibitors for the treatment of pathologies associated with necroptosis. ACS Med. Chem. Lett. 4(12), 1238-1243 (2013).