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Lenvatinib (E7080)

VEGFR inhibitor CAS# 417716-92-8

Lenvatinib (E7080)

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Chemical structure

Lenvatinib (E7080)

3D structure

Chemical Properties of Lenvatinib (E7080)

Cas No. 417716-92-8 SDF Download SDF
PubChem ID 9823820 Appearance Powder
Formula C21H19ClN4O4 M.Wt 426.85
Type of Compound N/A Storage Desiccate at -20°C
Synonyms E7080
Solubility Soluble in DMSO > 10 mM
Chemical Name 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide
SMILES COC1=CC2=NC=CC(=C2C=C1C(=O)N)OC3=CC(=C(C=C3)NC(=O)NC4CC4)Cl
Standard InChIKey WOSKHXYHFSIKNG-UHFFFAOYSA-N
Standard InChI InChI=1S/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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Lenvatinib (E7080)

DescriptionLenvatinib is an inhibitor of multiple RTK with IC50 values of 22 nM, 4 nM, 5.2 nM, 39 nM and 35 nM on VEGFR-1, VEGFR-2, VEGFR-3, PDGFRβ and RET, respectively.
TargetsVEGFR-1VEGFR-2VEGFR-3PDGFRβRET  
IC5022 nM4 nM5.2 nM39 nM35 nM  

Protocol

Kinase Assay [1]
Tyrosine kinase assays are performed by HTRF (KDR, VEGFR1, FGFR1, c-Met, EGFR) and ELISA (PDGFRβ), using the recombinant kinase domains of receptors. In both assays, 4 μL of serial dilutions of lenvatinib are mixed in a 96-well round plate with 10 μL of enzyme, 16 μL of poly (GT) solution (250 ng) and 10 μL of ATP solution (1 μM ATP) (final concentration of DMSO is 0.1%). In wells for blanks, no enzyme is added. In control wells no test article is added. The kinase reaction is initiated by adding ATP solution to each well. After 30-min incubation at 30°C, the reaction is stopped by adding 0.5mol/LEDTA (10 μL/well) to the reaction mixture in each well. Dilution buffer adequate to each kinase assay is added to the reaction mixture.

Cell Assay [1]
H146 (1.2×103 cells/50 μL/well) in SFM containing 0.5% BSA are cultured in 96-well multi-plates. After overnight culture at 37°C, SFM (150 μL/well) containing 0.5% FBS and several concentrations of SCF are added with or without several concentrations of compound. After culture for 72 hr, the ratios of surviving cells are measured by WST-1.

Animal Administration [1]
Female BALB/c nude mice (8-12 weeks old, 20-25 g) are maintained under clean-room conditions. H146 tumor cells (6.5×106) are implanted subcutaneously (s.c.) into the flank region of mice. Twelve days after inoculation, mice are randomized into control (n=12) and treatment (n=6 or n=5) groups and this point in time is identified as day 1. Lenvatinib and Imatinib, and VEGF neutralization antibody are suspended in 0.5% methylcellulose and saline, respectively, and administered orally twice a day for lenvatinib and imatinib and twice a week for antibody from day 1 to day 21. Tumor volume is measured on the indicated days and calculated. Antitumor activity is shown as a relative tumor volume (RTV=calculated tumor volume at indicated days/volume on day 1).

References:
[1]. Matsui J, et al. 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. 2008, 122(3), 664-671. [2]. Matsui J, et al. 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. 2008, 14(17),545 [3]. Glen H, et al. E7080, a multi-targeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer. 2011, 11, 309.

Lenvatinib (E7080) Dilution Calculator

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Lenvatinib (E7080) Molarity Calculator

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Preparing Stock Solutions of Lenvatinib (E7080)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3427 mL 11.7137 mL 23.4274 mL 46.8549 mL 58.5686 mL
5 mM 0.4685 mL 2.3427 mL 4.6855 mL 9.371 mL 11.7137 mL
10 mM 0.2343 mL 1.1714 mL 2.3427 mL 4.6855 mL 5.8569 mL
50 mM 0.0469 mL 0.2343 mL 0.4685 mL 0.9371 mL 1.1714 mL
100 mM 0.0234 mL 0.1171 mL 0.2343 mL 0.4685 mL 0.5857 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Lenvatinib (E7080)

Lenvatinib (E7080) is an inhibitor of multiple RTK with IC50 values of 22nM, 4nM, 5.2nM, 39nM and 35nM on VEGFR-1, VEGFR-2, VEGFR-3, PDGFRβ and RET, respectively [1].

Lenvatinib is presently under investigation both as monotherapy and in combination with cytotoxic agents for multiple types of solid tumor, including thyroid carcinoma and hepatocellular carcinoma (in Phase III trials), and melanoma, renal carcinoma, non-small cell lung carcinoma, glioblastoma multiforme, and ovarian and endometrial carcinoma (Phase I and II trials) [1].

When used as an inhibitor of RET kinase, Lenvatinib cause growth inhibition in TPC-1 cells and LC-2/ad cells. The GI50 values are 27nM and 48nM. It is also reported that Lenvatinib can inhibit RET (rearranged during transfection) gene fusion kinases, and inhibit oncogenic signaling of RET gene fusions. Lenvatinib has been demonstrated to exert antitumor activities in RET gene fusion-driven tumor models [2].

References:
[1] Neda Stjepanovic, Jaume Capdevila. Multikinase inhibitors in the treatment

of thyroid cancer: specific role of lenvatinib. Biologics: Targets and Therapy. 2014 (8): 129-139.

[2] Kiyoshi Okamoto, Kotaro Kodama, Kazuma Takase, Naoko Hata Sugi, Yuji Yamamoto, Masao Iwata, Akihiko Tsuruoka. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Letters. 2013 July(340):97-103.

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References on Lenvatinib (E7080)

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.[Pubmed:25913680]

Cancer. 2015 Aug 15;121(16):2749-56.

BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor alpha (PDGFRalpha), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After >/=14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. (c) 2015 American Cancer Society.

Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma.[Pubmed:26503473]

Oncotarget. 2015 Dec 15;6(40):43127-34.

OBJECTIVE AND METHODS: In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1-5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. RESULTS: Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) >/= 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD >/= 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. CONCLUSIONS: Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1-5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group.

Effects of Ketoconazole on the Pharmacokinetics of Lenvatinib (E7080) in Healthy Participants.[Pubmed:26097795]

Clin Pharmacol Drug Dev. 2015 Mar;4(2):155-160.

BACKGROUND: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein. METHODS: In this Phase I, single-center, randomized, open-label, two-period, crossover study, healthy adults (18-55 years; N = 18) were randomized to one of two sequences (ketoconazole --> placebo or vice versa). Ketoconazole (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Systemic exposure to lenvatinib increased slightly (15-19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration-time curve (AUC) was within the prespecified bioequivalence interval of 80-125%, Cmax slightly exceeded the 125% CI bound (134%). No changes in tmax, tlag, or t(1/2) were observed. Thirteen subjects (72%) experienced treatment-emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%). CONCLUSIONS: Lenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful.

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer.[Pubmed:26311725]

Clin Cancer Res. 2016 Jan 1;22(1):44-53.

PURPOSE: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). EXPERIMENTAL DESIGN: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. RESULTS: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. CONCLUSIONS: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

Description

Lenvatinib (E7080) is an oral, multi-targeted tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGFR, KIT, and RET, shows potent antitumor activities.

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