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Lenvatinib (E7080) Sale

(Synonyms: 仑伐替尼; E7080) 目录号 : GC15454

An inhibitor of VEGFR2 and VEGFR3

Lenvatinib (E7080) Chemical Structure

Cas No.:417716-92-8

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10mM (in 1mL DMSO)
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5mg
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25mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Kinase experiment [1]:

Preparation Method

4μL of serial dilutions of Lenvatinib (E7080) were mixed in a 96-well round plate with 10μL of enzyme (KDR), 16μL of poly (GT) solution (250 ng) and 10μL of ATP solution (1μmol/L ATP) (final concentration of DMSO was 0.1%).The kinase reaction was initiated by adding ATP solution to each well. After 30-min incubation at 30°C, the reaction was stopped by adding 0.5 mol/L EDTA (10μL/well) to the reaction mixture in each well. HTRF solution (50μL/well) was added to the reaction mixture, and then kinase activity was determined by measurement of fluorescence with a time-resolved fluorescence detector at an excitation wavelength of 337 nm and an emission wave-lengths of 620 and 665 nm.

Reaction Conditions

4μL,30 min

Applications

Lenvatinib (E7080) inhibited KDR with IC50 values of 4.0 nM.

Cell experiment [2]:

Cell lines

8505C and TCO1 cell

Preparation Method

The cells were grown in 96-well microplates in a final volume of 100 μL culture medium per well. The cells were incubated with 0.1 to 50 μM Lenvatinib (E7080) for 48 h. Then, 50 μL of the XTT labeling mixture was added to each well to a final XTT concentration of 0.3 mg/mL. After incubation of the microplate for 4 h in 5% CO2 at 37 °C in a humidified incubator, the formazan dye formed was quantified using a scanning multiwell spectrophotometer.

Reaction Conditions

0.1 to 50 μM Lenvatinib (E7080) for 48 h

Applications

The half-maximal inhibitory concentrations (IC50) for Lenvatinib (E7080) treatment of 8505C and TCO1 cells were 24.26 and 26.32 μM, respectively.

Animal experiment [1]:

Animal models

Female BALB/c nude mice (8–12 weeks old, 20–25 g)

Preparation Method

H146 tumor cells (6.5×106) were implanted subcutaneously into the flank region of mice. Twelve days after inoculation, mice were randomized into control (n=12) and treatment groups (n=6) and this point in time was identified as day 1. Lenvatinib (E7080) were suspended in 0.5% methylcellulose and saline, and administered orally twice a day for Lenvatinib (E7080) from day 1 to day 21. Tumor volume was measured on the indicated days and calculated.

Dosage form

Administer orally twice a day for Lenvatinib (E7080)

Applications

Oral administration of Lenvatinib (E7080) inhibited the growth of H146 tumor at 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg.

References:

[1]. Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, Uenaka T, Asada M. 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 Feb 1;122(3):664-71.

[2]. Enomoto K, Hirayama S, Kumashiro N, Jing X, Kimura T, Tamagawa S, Matsuzaki I, Murata SI, Hotomi M. Synergistic Effects of Lenvatinib (E7080) and MEK Inhibitors against Anaplastic Thyroid Cancer in Preclinical Models. Cancers (Basel). 2021 Feb 18;13(4):862.

产品描述

E7080, known as lenvatinib, is an oral multitargeted tyrosine kinase inhibitor including VEGF, FGF and SCF receptors that has been shown to improve the survival rate of patients with radioiodine-refractory thyroid cancer. Lenvatinib (E7080) had antitumor activity against HCC PDX models, likely through its potent anti-angiogenic activity [1].

Lenvatinib (E7080) inhibited Flt-1, KDR, Flt-4 with IC50 values of 22, 4.0 and 5.2 nM, respectively. Lenvatinib (E7080) inhibited FGFR1 and FDGFR tyrosine kinases. In addition to these kinases, Lenvatinib (E7080) also inhibited KIT kinase with an IC50 value of 100 nM [2]. The half-maximal inhibitory concentrations (IC50 ) for Lenvatinib (E7080) treatment of 8505C and TCO1 cells were 24.26 and 26.32 μM, respectively [3].

The novel multi-targeted kinase inhibitor Lenvatinib (E7080), which inhibited both KDR and KIT kinases, showed a more potent antitumor efficacy against H146 tumor than imatinib. Oral administration of Lenvatinib (E7080) inhibited the growth of H146 tumor at 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg [2]. Lenvatinib (E7080) at 10 and 30 mg/kg inhibited the tumor growth of both PDXs, LI0050 and LI0334 [1]. Lenvatinib (E7080), as compared with placebo, was associated with significant prolongation of progression-free survival and an improved response rate (64.8% vs. 1.5%) among patients with iodine-131–refractory differentiated thyroid cancer [4].

References:
[1].Matsuki M, Hoshi T, Yamamoto Y, Ikemori-Kawada M, Minoshima Y, Funahashi Y, Matsui J. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med. 2018 Jun;7(6):2641-2653.
[2].Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, Uenaka T, Asada M. 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 Feb 1;122(3):664-71.
[3].Enomoto K, Hirayama S, Kumashiro N, Jing X, Kimura T, Tamagawa S, Matsuzaki I, Murata SI, Hotomi M. Synergistic Effects of Lenvatinib (E7080) and MEK Inhibitors against Anaplastic Thyroid Cancer in Preclinical Models. Cancers (Basel). 2021 Feb 18;13(4):862.
[4].Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12;372(7):621-30.

E7080,称为乐伐替尼,是一种口服多靶点酪氨酸激酶抑制剂,包括 VEGF、FGF 和 SCF 受体,已被证明可以提高放射性碘难治性甲状腺癌患者的生存率。 Lenvatinib (E7080) 对 HCC PDX 模型具有抗肿瘤活性,这可能是通过其有效的抗血管生成活性[1]

Lenvatinib (E7080) 抑制 Flt-1、KDR、Flt-4,IC50 值分别为 22、4.0 和 5.2 nM。 Lenvatinib (E7080) 抑制 FGFR1 和 FDGFR 酪氨酸激酶。除了这些激酶,乐伐替尼 (E7080) 还抑制 KIT 激酶,IC50 值为 100 nM [2]。 Lenvatinib (E7080) 处理 8505C 和 TCO1 细胞的半数最大抑制浓度 (IC50 ) 分别为 24.26 和 26.32 μM [3]

新型多靶点激酶抑制剂乐伐替尼 (Lenvatinib) (E7080) 可同时抑制 KDR 和 KIT 激酶,对 H146 肿瘤显示出比伊马替尼更有效的抗肿瘤功效。口服乐伐替尼 (E7080) 在 30 和 100 mg/kg 时以剂量依赖性方式抑制 H146 肿瘤的生长,在 100 mg/kg 时引起肿瘤消退 [2]。 10 和 30 mg/kg 的乐伐替尼 (E7080) 抑制了 PDX、LI0050 和 LI0334 的肿瘤生长[1]。与安慰剂相比,乐伐替尼 (E7080) 与碘 131 难治性分化型甲状腺癌患者的无进展生存期显着延长和缓解率提高(64.8% 对 1.5%)相关[4] .

Chemical Properties

Cas No. 417716-92-8 SDF
别名 仑伐替尼; E7080
化学名 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide
Canonical SMILES COC1=CC2=NC=CC(=C2C=C1C(=O)N)OC3=CC(=C(C=C3)NC(=O)NC4CC4)Cl
分子式 C21H19ClN4O4 分子量 426.85
溶解度 DMSO: 8.33 mg/mL (15.93 mM) 储存条件 Store at 4°C, protect from light
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Research Update

Lenvatinib: A Review in Hepatocellular Carcinoma

Lenvatinib (Lenvima?) is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China. The approval of lenvatinib was based on results of the randomized, open-label, multinational, non-inferiority phase III REFLECT trial in patients with unresectable HCC, who had not received treatment for advanced disease. In REFLECT, lenvatinib was non-inferior, but not superior, to sorafenib (current standard of care) for overall survival (OS). However, lenvatinib was associated with significant improvements compared with sorafenib in terms of all secondary endpoints [higher objective response rate (ORR), and longer progression-free survival (PFS) and time to progression (TTP)]. Lenvatinib had a generally manageable tolerability profile in REFLECT, with the most common treatment-emergent adverse events being hypertension, diarrhoea, decreased appetite and decreased weight. Given its non-inferior efficacy to sorafenib and manageable tolerability profile, lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC. Further clinical experience may be required to fully define the position of lenvatinib in this setting.

Lenvatinib versus placebo in radioiodine-refractory thyroid cancer

Background: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).
Methods: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.
Results: The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.
Conclusions: Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy

Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma (HCC). Its application has changed the status of sorafenib as the only first-line TKI treatment for HCC for more than a decade. Evidence has shown that lenvatinib possesses antitumor proliferation and immunomodulatory activity in preclinical studies. In comparison, lenvatinib was non-inferior to sorafenib in overall survival (OS), and even shows superiority with regard to all the secondary efficacy endpoints. Immune-checkpoint inhibitors(ICIs)are now being incorporated into HCC treatment. Positive outcomes have been achieved in the combination of lenvatinib plus ICIs, bringing broader prospects for HCC. This review presents an overview on the therapeutic mechanisms and clinical efficacy of lenvatinib in HCC, and we discuss the future perspectives of lenvatinib in HCC management with focus on biomarker-guided precision medicine.

Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC

Background and aims: Recently, clinical trials of lenvatinib plus pembrolizumab in HCC have displayed an impressive objective response rate. This study aimed to clarify the mechanism for optimal patient selection.
Approach and results: First, in patients with HCC, lenvatinib-treated recurrent tumors had lower programmed death ligand 1 (PD-L1) expression and regulatory T cell (Treg) infiltration compared with matched primary tumors. Consistently, in C57BL/6 wild-type mice receiving anti-programmed cell death 1 (PD-1) therapy, PD-L1 expression and Treg infiltration in s.c. tumors were reduced when adding lenvatinib to the scheme. Mechanistically, on the one hand, FGF receptor 4 (FGFR4) was the most pivotal target in PD-L1 down-regulation by lenvatinib in vitro. Furthermore, lenvatinib reinforced the proteasomal degradation of PD-L1 by blocking the FGFR4-glycogen synthase kinase 3β axis and rescued the sensitivity of interferon-γ-pretreated HCC cells to T-cell killing by targeting FGFR4. On the other hand, the level of IL-2 increased after anti-PD-1 treatment, but IL-2-mediated Treg differentiation was blocked by lenvatinib through targeting FGFR4 to restrain signal transducer and activator of transcription 5 (STAT5) phosphorylation. By regulating the variations in the number of Tregs and the tumor FGFR4 level in C57BL/6-forkhead box protein P3 (Foxp3DTR ) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high levels of FGFR4 and Foxp3 conferred immune tolerance but better response to the combined therapy in patient cohorts.
Conclusions: Lenvatinib reduced tumor PD-L1 level and Treg differentiation to improve anti-PD-1 efficacy by blocking FGFR4. Levels of FGFR4 expression and Treg infiltration in tumor could serve as biomarkers for screening patients with HCC using lenvatinib plus anti-PD-1 combination therapy.

STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib

Background: Dysregulation of both mitochondrial biogenesis and mitophagy is critical to sustain oncogenic signaling pathways. However, the mechanism of mitophagy in promoting hepatocellular carcinoma (HCC) progression remains poorly understood. In this study, we investigated the clinical significance and biological involvement of mitochondrial inner membrane protein STOML2 in HCC.
Methods: STOML2 was identified by gene expression profiles of HCC tissues and was measured in tissue microarray and cell lines. Gain/loss-of-function experiment was applied to study the biological function of STOML2 in HCC. Flow cytometry, Western blotting, laser confocal microscopy, transmission electron microscopy, and co-immunoprecipitation were used to detect and analyze mitophagy. ChIP and luciferase reporter assay were conducted to evaluate the relationship between STOML2 and HIF-1α. The sensitivity to lenvatinib was assessed in HCC both in vitro and in vivo.
Results: Increased expression of STOML2 was found in HCC compared with paired peritumoral tissues. It was more significant in HCC with metastasis and correlated with worse overall survival and higher probability of recurrence after hepatectomy. Upregulation of STOML2 accelerated HCC cells colony formation, migration and invasion. Mechanically, TCGA dataset-based analysis showed enrichment of autophagy-related pathways in STOML2 highly-expressed HCC. Next, STOML2 was demonstrated to interact and stabilize PINK1 under cellular stress, amplify PINK1-Parkin-mediated mitophagy and then promote HCC growth and metastasis. Most interestingly, HIF-1α was upregulated and transcriptionally increased STOML2 expression in HCC cells under the treatment of lenvatinib. Furthermore, higher sensitivity to lenvatinib was found in HCC cells when STOML2 was downregulated. Combination therapy with lenvatinib and mitophagy inhibitor hydroxychloroquine obtained best efficacy.
Conclusions: Our findings suggested that STOML2 could amplify mitophagy through interacting and stabilizing PINK1, which promote HCC metastasis and modulate the response of HCC to lenvatinib. Combinations of pharmacologic inhibitors that concurrently block both angiogenesis and mitophagy may serve as an effective treatment for HCC.