Nintedanib, Ethanesulfonate Salt

Solubility: Soluble in DMSO at 25 mg/mL with warming, soluble in ethanol at 8 mg/mL with warming, soluble in water at 25 mg/mL with warming, buffers, serum, or other additives may increase or decrease the aqueous solubility. This research compound is the ethanesulfonate salt form of nintedanib. Nintedanib is an indolinone derivative that potently inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) kinase activity in enzymatic assays. It blocks mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, namely endothelial cells, pericytes, and smooth muscle cells, and it inhibits cell proliferation with an EC50 of 10-80 nM. Hilberg, F., et al. 'BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.' Cancer Res. 68: 4774-4782 (2008). Table 1. In vitro kinase inhibition profile of Nintedanib (adapted from Hilberg, F., et al. 2008). Kinase IC50 (nM)* VEGFR-2 (mouse) 13 ± 4 VEGFR-3 13 ± 10 Lck 16 ± 16 VEGFR-2 21 ± 13 Flt-3 26 VEGFR-1 34 ± 15 FGFR-2 37 ± 2 PDGFRalpha 59 ± 71 PDGFRbeta 65 ± 7 FGFR-1 69 ± 70 FGFR-3 108 ± 41 Src 156 ± 40 Lyn 195 ± 12 FGFR-4 610 ± 117 IGF1R >1,000 InsR >4,000 CDK1 >10,000 CDK2 >10,000 CDK4 >10,000 Other kinases (n = 26) >10,000 EGFR >50,000 HER2 >50,000 * Assays performed with ATP concentrations at the respective Ki. Human kinases were tested except when stated otherwise. Phosphatase PP2A and another 25 kinases were analyzed at 10 µM with 100 µM ATP: GSK3B, ROCKII, DYRK1A, PKCalpha, MAPK2ERK2, HGFR, MSK1, PDK1, CHK1, MAPKAPK2, SAPK2AP38, S6K1, SGK, CK1, CK2, PKA, SAPK2BP38B2, SAPK3P38G, JNK1A1, SAPK4P38D, PHK, PKBA, CSK, CDK2/CYCLINA, PRAK (data not shown). Nintedanib significantly decreased blood vessel area and inhibited tumour growth. Zips, D., et al. 'Triple angiokinase inhibition, tumour hypoxia and radiation response of FaDu human squamous cell carcinomas.' Radiother. Oncol. 92: 405-410 (2009). A reproducible hepatic perfusion index (HPI) was determined by using quantified gadopentetate dimeglumine (Gd-DTPA) concentration. The HPI decreased significantly at 28 days after treatment with nintedanib. HPI may be useful for monitoring antiangiogenic treatment response of hepatic metastases. Miyazaki, K., et al. 'Quantitative mapping of hepatic perfusion index using MR imaging: a potential reproducible tool for assessing tumour response to treatment with the antiangiogenic compound BIBF 1120, a potent triple angiokinase inhibitor.' Eur. Radiol. 18: 1414-1421 (2008).