119. Zhang C, Tan C, Ding H et al (2012) Selective VEGFR inhibitors for anticancer therapeutics in
clinical use and clinical trials. Curr Pharm Des 18:2921–2935. https://doi.org/10.2174/
138161212800672732
120. Matsui J, Yamamoto Y, Funahashi Y et al (2008) E7080, a novel inhibitor that targets multiple
kinases, has potent antitumour activities against stem cell factor producing human small cell
lung cancer H146, based on angiogenesis inhibition. Int J Cancer 122:664–671. https://doi.
org/10.1002/ijc.23131
121. Okamoto K, Ikemori-Kawada M, Jestel A et al (2014) Distinct binding mode of multikinase
inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett 6:89–94.
https://doi.org/10.1021/ml500394m
122. Roskoski R (2016) Classification of small molecule protein kinase inhibitors based upon the
structures of their drug-enzyme complexes. Pharmacol Res 103:26–48. https://doi.org/10.
1016/j.phrs.2015.10.021
123. Boss DS, Glen H, Beijnen JH et al (2012) A phase I study of E7080, a multitargeted tyrosine
kinase inhibitor, in patients with advanced solid tumours. Br J Cancer 106:1598–1604. https://
doi.org/10.1038/bjc.2012.154
124. Inoue K, Mizuo H, Kawaguchi S et al (2014) Oxidative metabolic pathway of lenvatinib
mediated by aldehyde oxidase. Drug Metab Dispos 42:1326–1333. https://doi.org/10.1124/
dmd.114.058073
125. Shumaker R, Aluri J, Fan J et al (2015) Effects of ketoconazole on the pharmacokinetics of
lenvatinib (E7080) in healthy participants. Clin Pharmacol Drug Dev 4:155–160. https://doi.
org/10.1002/cpdd.140
126. Shumaker RC, Aluri J, Fan J et al (2014) Effect of rifampicin on the pharmacokinetics of
lenvatinib in healthy adults. Clin Drug Investig 34:651–659. https://doi.org/10.1007/s40261014-0217-y
127. Matsui J, Funahashi Y, Uenaka T et al (2008) Multi-kinase inhibitor E7080 suppresses lymph
node and lung metastases of human mammary breast tumour MDA-MB-231 via inhibition of
vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer
Res 14:5459–5465. https://doi.org/10.1158/1078-0432.CCR-07-5270
128. Scott LJ (2015) Lenvatinib: first global approval. Drugs 75:553–560
129. Tohyama O, Matsui J, Kodama K et al (2014) Antitumour activity of lenvatinib (E7080): an
angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human
thyroid Cancer models. J Thyroid Res 2014:1–13. https://doi.org/10.1155/2014/638747. ID
638747
130. Frampton JE (2016) Lenvatinib: a review in refractory thyroid Cancer. Target Oncol
11:115–122
131. Schlumberger M, Tahara M, Wirth LJ et al (2015) Lenvatinib versus placebo in radioiodinerefractory thyroid Cancer. N Engl J Med 372:621–630. https://doi.org/10.1056/
NEJMoa1406470
132. Cao Y (2013) Multifarious functions of PDGFs and PDGFRs in tumour growth and metastasis. Trends Mol Med 19:460–473. https://doi.org/10.1016/j.molmed.2013.05.002
133. Heldin C-H (2013) Targeting the PDGF signaling pathway in tumour treatment. Cell Commun
Signal 11:97. https://doi.org/10.1186/1478-811X-11-97
134. Lewis NL, Lewis LD, Eder JP et al (2009) Phase I study of the safety, tolerability, and
pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor
tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 27:5262–5269.
https://doi.org/10.1200/JCO.2009.21.8487
135. Chen P-HH, Chen X, He X (2013) Platelet-derived growth factors and their receptors:
structural and functional perspectives. Biochim Biophys Acta 1834:2176–2186. https://doi.
org/10.1016/j.bbapap.2012.10.015
136. Michael M, Vlahovic G, Khamly K et al (2010) Phase Ib study of CP-868,596, a PDGFR
inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor. Br J Cancer
103:1554–1561. https://doi.org/10.1038/sj.bjc.6605941
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
199
clinical use and clinical trials. Curr Pharm Des 18:2921–2935. https://doi.org/10.2174/
138161212800672732
120. Matsui J, Yamamoto Y, Funahashi Y et al (2008) E7080, a novel inhibitor that targets multiple
kinases, has potent antitumour activities against stem cell factor producing human small cell
lung cancer H146, based on angiogenesis inhibition. Int J Cancer 122:664–671. https://doi.
org/10.1002/ijc.23131
121. Okamoto K, Ikemori-Kawada M, Jestel A et al (2014) Distinct binding mode of multikinase
inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett 6:89–94.
https://doi.org/10.1021/ml500394m
122. Roskoski R (2016) Classification of small molecule protein kinase inhibitors based upon the
structures of their drug-enzyme complexes. Pharmacol Res 103:26–48. https://doi.org/10.
1016/j.phrs.2015.10.021
123. Boss DS, Glen H, Beijnen JH et al (2012) A phase I study of E7080, a multitargeted tyrosine
kinase inhibitor, in patients with advanced solid tumours. Br J Cancer 106:1598–1604. https://
doi.org/10.1038/bjc.2012.154
124. Inoue K, Mizuo H, Kawaguchi S et al (2014) Oxidative metabolic pathway of lenvatinib
mediated by aldehyde oxidase. Drug Metab Dispos 42:1326–1333. https://doi.org/10.1124/
dmd.114.058073
125. Shumaker R, Aluri J, Fan J et al (2015) Effects of ketoconazole on the pharmacokinetics of
lenvatinib (E7080) in healthy participants. Clin Pharmacol Drug Dev 4:155–160. https://doi.
org/10.1002/cpdd.140
126. Shumaker RC, Aluri J, Fan J et al (2014) Effect of rifampicin on the pharmacokinetics of
lenvatinib in healthy adults. Clin Drug Investig 34:651–659. https://doi.org/10.1007/s40261014-0217-y
127. Matsui J, Funahashi Y, Uenaka T et al (2008) Multi-kinase inhibitor E7080 suppresses lymph
node and lung metastases of human mammary breast tumour MDA-MB-231 via inhibition of
vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer
Res 14:5459–5465. https://doi.org/10.1158/1078-0432.CCR-07-5270
128. Scott LJ (2015) Lenvatinib: first global approval. Drugs 75:553–560
129. Tohyama O, Matsui J, Kodama K et al (2014) Antitumour activity of lenvatinib (E7080): an
angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human
thyroid Cancer models. J Thyroid Res 2014:1–13. https://doi.org/10.1155/2014/638747. ID
638747
130. Frampton JE (2016) Lenvatinib: a review in refractory thyroid Cancer. Target Oncol
11:115–122
131. Schlumberger M, Tahara M, Wirth LJ et al (2015) Lenvatinib versus placebo in radioiodinerefractory thyroid Cancer. N Engl J Med 372:621–630. https://doi.org/10.1056/
NEJMoa1406470
132. Cao Y (2013) Multifarious functions of PDGFs and PDGFRs in tumour growth and metastasis. Trends Mol Med 19:460–473. https://doi.org/10.1016/j.molmed.2013.05.002
133. Heldin C-H (2013) Targeting the PDGF signaling pathway in tumour treatment. Cell Commun
Signal 11:97. https://doi.org/10.1186/1478-811X-11-97
134. Lewis NL, Lewis LD, Eder JP et al (2009) Phase I study of the safety, tolerability, and
pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor
tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 27:5262–5269.
https://doi.org/10.1200/JCO.2009.21.8487
135. Chen P-HH, Chen X, He X (2013) Platelet-derived growth factors and their receptors:
structural and functional perspectives. Biochim Biophys Acta 1834:2176–2186. https://doi.
org/10.1016/j.bbapap.2012.10.015
136. Michael M, Vlahovic G, Khamly K et al (2010) Phase Ib study of CP-868,596, a PDGFR
inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor. Br J Cancer
103:1554–1561. https://doi.org/10.1038/sj.bjc.6605941
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
199