417716-92-8 Usage
Thyroid cancer drugs
Lenvatinib is a thyroid cancer drug developed by Eisai Corporation of Japan (Code: E7080), belonging to the inhibitor of oral multi-receptor tyrosine kinase (RTK) and can inhibit the kinase activity of the vascular endothelial growth factor (VEGF) Receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib can also inhibit the involvement of other RTKs in pathological angiogenesis, tumor growth, and cancer progression except for their normal cellular functions including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor (PDGFR [alpha]), KIT, and RET.
[Indications]: Lenvatinib is suitable for the treatment of patients of thyroid cancer of local recurrence or metastasis type, progressivity type and radioactive iodine-refractory differentiated type.
On February 13, 2015, the US FDA approved anticancer drug Lenvatinib for the treatment of thyroid cancer. Lenvatinib is a multi-target enzyme inhibitor, being capable of inhibiting the VEGFR2 and VEGFR3 (vascular endothelial growth factor receptor). The trade name of Lenvatinib is Lenvima.
On May 20, 2015, the European Medicines Agency (EMA) approved Lenvatinib for the treatment of invasive, locally advanced or metastatic differentiated (papillary, follicular, Hurthle type) thyroid cancer (DTC). In the trial, the median survival time for patients of radioactive iodine-refractory DTC treated with Lenvatinib was 18 months while the value for patients who take placebo is only 3 months.
In Europe, Lenvatinib will compete with Bayer's kinase inhibitor sorafenib (trade name: Nexavar), which had been respectively approved by EMA and the US Food and Drug Administration for the treatment of radioactive iodine refractory DTC in 2014 and 2013, respectively. At the time, Sorafenib had been reported to be the first targeted therapeutics to be marketed for the past 40 years in the treatment of refractory DTCs. The marketing applications of Lenvatinib in Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil are also under review.
Information regarding the pharmacological effects, clinical evaluation, and indication of the thyroid cancer drug Lenvatinib were compiled and edited by Tongtong from lookchem (2015-09-22).
Biological activity
Lenvatinib (E7080) is a multi-target inhibitor with the most potent effect on VEGFR2 (KDR)/VEGFR3 (Flt-4) with an IC50 of 4 nM/5.2 and weaker effect on VEGFR1/Flt-1. The selectivity of targeting on VEGFR 2/ 3 is about 10 times as high as that of targeting on FGFR1 and PDGFRα/β. Phase 3.
In vitro study
E7080 can effectively inhibit the angiogenesis, also significantly inhibit the VEGF/KDR and SCF/KIT signaling pathway. Based on the in vitro receptor tyrosine and serine/threonine kinase assays, the IC50 of E7080 in inhibiting Flt-1, KDR, and Flt-4 were 22, 4.0 and 5.2 nM, respectively. In addition to these kinases, E7080 can also inhibit FGFR1 and PDGFR tyrosine kinases, acting on FGFR1, PDGFRα and PDGFRβ with IC50 values of 46, 51 and 100 nM, respectively. When E7080 acted respectively on HUVECs stimulated by VEGF and VEGF-C, respectively, and effectively inhibit VEGFR2 and VEGFR3 phosphorylation with IC50 of 0.83 nM and 0.36 nM, respectively. Recent studies have shown that treatment with 1 μM and 10 μM and E7080, through inhibiting the FGFR and PDGFR signaling pathway, can significantly inhibit cell migration and invasion.
In vivo studies
Orally administration of E7080 at a dose of 30 mg/kg and 100 mg/kg for the treatment of H146 xenograft tumor model can inhibit the tumor growth in a dose-dependent manner. At 100 mg/kg, it can result in tumor regression. Moreover, treatment with a dose of 100 mg/kg of E7080, compared with the VEGF antibody and Imatinib treatment, can reduce the microvascular density more.
Feature
E7080 is an orally active multi-target kinase inhibitor.
Description
Lenvatinib is an inhibitor of the receptor tyrosine kinases VEGF receptor 2 (VEGFR2) and VEGFR3 (IC50s = 4 and 5.2 nM, respectively). It also inhibits the related kinases VEGFR1, FGFR1, PDGFRα, PDGFRβ and Kit (IC50s = 22, 46, 51, 39, and 100 nM, respectively). Lenvatinib (30 mg/kg, twice per day) reduces tumor growth in an H146 small cell lung cancer mouse xenograft model and induces tumor regression when administered at a dose of 100 mg/kg twice per day. Formulations containing lenvatinib have been used in the treatment of differentiated thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma.
Uses
Different sources of media describe the Uses of 417716-92-8 differently. You can refer to the following data:
1. E7080 (Lenvatinib) is a multi-target inhibitor of VEGFR2 and VEGFR3 with IC50 of 4 nM and 5.2 nM, respectively.
2. Lenvatinib is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors.
Definition
ChEBI: A member of the class of quinolines that is the carboxamide of 4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxyquinoline-6-carboxylic acid. A multi-kinase inhibitor and orphan drug used (as its mesylate salt) for the treatment of various types
of thyroid cancer that do not respond to radioiodine.
References
1) Matsui et al. (2008), E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition; Int. J. Cancer, 122 664
2) Matsui et al. (2008), Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R)2 and VEGF-R3 kinase; Clin. Cancer Res., 14 5459
3) Glen et al. (2011), E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion; BMC Cancer, 11 309
4) Yamamoto et al. (2014), Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage; Vasc. Cell, 6 18
Check Digit Verification of cas no
The CAS Registry Mumber 417716-92-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,1,7,7,1 and 6 respectively; the second part has 2 digits, 9 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 417716-92:
(8*4)+(7*1)+(6*7)+(5*7)+(4*1)+(3*6)+(2*9)+(1*2)=158
158 % 10 = 8
So 417716-92-8 is a valid CAS Registry Number.
InChI:InChI=1/C21H19ClN4O4/c1-29-19-10-17-13(9-14(19)20(23)27)18(6-7-24-17)30-12-4-5-16(15(22)8-12)26-21(28)25-11-2-3-11/h4-11H,2-3H2,1H3,(H2,23,27)(H2,25,26,28)
417716-92-8Relevant articles and documents
Preparation method of lenvatinib and preparation method of lenvatinib intermediate
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Paragraph 0117; 0122-0123; 0134-0136, (2021/07/01)
The invention discloses a preparation method of lenvatinib and a preparation method of a lenvatinib intermediate. The preparation method of an amide compound as shown in a formula II comprises the following step: in a solvent, carrying out amidation react
Synthetic method of anti-cancer drug lenvatinib
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Paragraph 0010, (2021/01/25)
The invention provides a synthetic method of an anti-cancer drug lenvatinib. The synthetic method comprises the following steps of synthesis of a compound 2, synthesis of a compound 4, synthesis of acompound 5, synthesis of a compound 6, synthesis of a compound 7, synthesis of a compound 8, synthesis of a compound 9, synthesis of a compound 10, synthesis of a compound 11 and synthesis of a compound 12. Synthesis of a compound 2 is as follows: sequentially adding raw materials of Meldrum's acid (40g, 277.8 mmol) and trimethyl orthoformate (147g, 1.387 mol) into a 500ml of three-neck flask, slowly performing heating to 90 DEG C for reaction under a stirring condition, slowly performing cooling to room temperature under a solution stirring condition after the reaction is finished, performingfiltering after crystallization, recrystallizing a product by using petroleum ether/ethyl acetate according to a ratio of 5: 1, and performing drying to obtain a faint yellow product 2; by improvingthe synthesis method of the anti-cancer drug lenvatinib, the synthesis method has the advantages of reasonable design, simple operation flow, easily available raw materials, stable yield and easinessin industrial production, so that the problems and defects of the synthesis method are effectively solved and overcome.
Synthesis method of lenvatinib and new intermediate
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Paragraph 0049; 0059-0061, (2020/07/24)
The invention discloses a synthesis method of lenvatinib and a new intermediate. The method comprises the following steps: step 1, taking 4-amino-3-chlorophenol hydrochloride and 4-chloro-7-methoxy-6-amido quinoline as initial raw materials, and carrying
