TAS-115
(Synonyms: TAS-115) 目录号 : GC33173
A multi-kinase inhibitor
Cas No.:1190836-34-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Enzyme inhibition studies are performed using a mobility shift assay. Briefly, 0.3 μg/mL of recombinant MET (rMET, N-terminal glutathione S-transferase (GST) Tag) and 1.5 μM of FL-Peptide 2 or 2 μg/mL of recombinant VEGFR2 (rVEGFR2, amino acid 790-end, N-terminal 6His Tagged) and 1.5 μM of FL-Peptide 22 are added to a 25 μL mixture containing 1/2 the Michaelis constant (Km) level of ATP, 100 mM of HEPES (pH 7.2), 0.003% (w/v) Brij35, 0.04% (v/v) Tween 20, 10 mM of MgCl2, 1 mM of dithiothreitol, a Complete Mini EDTA-free Protease Inhibitor Cocktail Tablet, and a PhosSTOP Phosphatase Inhibitor Cocktail Tablet, with the addition of 0.05% (w/v) CHAPSO only in the case of rVEGFR2. The reaction mixture is incubated for 90 minutes at 28°C and is stopped by the addition of 15 mM of EDTA. Phosphorylated peptide is calculated using a LabChip EZ Reader, Version 2.1.82.0 (UCC Version: 1.96, CCD Version: 102). On the basis of the amount of phosphorylated peptide formed in the control well and the drug-treated well, the 50% inhibitory concentration (IC50) is calculated using a logistic regression analysis. A total of 192 kinase panel assays is performed using the ProfilerPro Kit 1-8 and is analyzed using a mobility shift assay. |
Cell experiment: | Cell growth is measured using the MTT dye reduction method. Tumor cells are plated into 96-well plates at a density of 2×103 cells/100 mL RPMI-1640 medium with 10% FBS per well. After 24-hour incubation, various reagents are added to each well, and the cells incubated for a further 72 hours, followed by the addition of 50 μL of MTT solution (2 mg/mL) to each well and incubation for 2 hours. The media containing MTT solution is removed, and the dark blue crystals are dissolved by adding 100 mL of dimethyl sulfoxide. The absorbance of each well is measured with a microplate reader at test and reference wavelengths of 550 and 630 nm, respectively. The percentage of growth is shown relative to untreated controls. Each reagent concentration is tested at least in triplicate during each experiment, and each experiment is conducted at least three times. |
Animal experiment: | A SC-9 fragment is implanted subcutaneously into the right abdomen of each mouse via a trocar. Suspensions of MKN45 cells are prepared and are implanted subcutaneously into the right abdomen of each nude mouse. The tumor volume (TV, mm3) is calculated. The TAS-115 dose levels are set at 12.5, 50, and 200 mg/kg/d. The dose level for sunitinib is set at 40 mg/kg/d; this dose is equivalent to the maximum tolerated dose (MTD). Oral drug treatment is continued for 14 or 42 consecutive days for the chronic dosing in the SC-9 xenograft model. During the treatment period, TV and body weight are measured twice per week. |
References: [1]. Fujita H, et al. The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile. Mol Cancer Ther. 2013 Dec;12(12):2685-96. | |
TAS 115 is a multi-kinase inhibitor that inhibits the growth factor receptors PDGFRα and PDGFRβ (IC50s = 0.81 and 7.06 nM, respectively), c-FMS (IC50 = 15 nM), VEGFR2 and VEGFR1 (IC50s = 30 and 140 nM, respectively), Met (IC50 = 32 nM), and FGFR2 (IC50 = 340 nM).1,2 It also inhibits Axl, c-Kit, Src, and FLT1.1 TAS 115 inhibits VEGF-induced VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) and Met phosphorylation in Met-amplified MKN45 human gastric cancer cells. It also inhibits VEGF-dependent, but not VEGF-independent, growth of HUVECs (IC50s = 0.019 and 19.3 ?M, respectively) and of Met-amplified MKN45, but not Met-inactivated, human MCF-7 breast cancer cells (GI50s = 0.032 and >10 ?M, respectively). TAS 115 reduces tumor growth in a MKN45 mouse xenograft model (ED50 = 8 mg/kg).
1.Fujita, H., Miyadera, K., Kato, M., et al.The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profileMol. Cancer Ther.12(12)2685-2696(2013) 2.Koyama, K., Goto, H., Morizumi, S., et al.The tyrosine kinase inhibitor TAS-115 attenuates bleomycin-induced lung fibrosis in miceAm. J. Respir. Cell Mol. Biol.60(4)478-487(2019)
| Cas No. | 1190836-34-0 | SDF | |
| 别名 | TAS-115 | ||
| Canonical SMILES | O=C(C1=C(OC)C=C2N=CC=C(OC3=CC=C(NC(NC(CC4=CC=CC=C4)=O)=S)C=C3F)C2=C1)NC | ||
| 分子式 | C27H23FN4O4S | 分子量 | 518.56 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.9284 mL | 9.6421 mL | 19.2842 mL |
| 5 mM | 0.3857 mL | 1.9284 mL | 3.8568 mL |
| 10 mM | 0.1928 mL | 0.9642 mL | 1.9284 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
TAS-115 inhibits PDGFRα/AXL/FLT-3 signaling and suppresses lung metastasis of osteosarcoma
FEBS Open Bio 2020 May;10(5):767-779.PMID:32128992DOI:10.1002/2211-5463.12827.
Osteosarcoma is the most common malignant bone tumor in adolescence and childhood. Metastatic osteosarcoma has a poor prognosis with an overall 5-year survival rate of approximately 20%. TAS-115 is a novel multiple receptor tyrosine kinase inhibitor that is currently undergoing clinical trials. Using the mouse highly lung-metastatic osteosarcoma cell line, LM8, we showed that TAS-115 suppressed the growth of subcutaneous grafted tumor and lung metastasis of osteosarcoma at least partially through the inhibition of platelet-derived growth factor receptor alpha, AXL, and Fms-like tyrosine kinase 3 phosphorylation. We also show that these signaling pathways are activated in various human osteosarcoma cell lines and are involved in proliferation. Our results suggest that TAS-115 may have potential for development into a novel treatment for metastatic osteosarcoma.
The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice
Am J Respir Cell Mol Biol 2019 Apr;60(4):478-487.PMID:30540913DOI:10.1165/rcmb.2018-0098OC.
The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.
Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study
Invest New Drugs 2021 Dec;39(6):1559-1567.PMID:34117970DOI:10.1007/s10637-021-01107-4.
Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013).
Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma
BMC Cancer 2017 May 16;17(1):334.PMID:28511645DOI:10.1186/s12885-017-3324-3.
Background: The prognosis of synovial sarcoma (SS), an aggressive soft tissue sarcoma, remains poor. We previously reported that c-MET or platelet-derived growth factor receptor α (PDGFRα) signalling pathway is related to SS progression based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays. TAS-115 is a novel c-MET/ vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitor that has been shown to inhibit multiple RTKs. Here we aimed to investigate the therapeutic potential of TAS-115 against SS. Methods: We first evaluated which signalling pathway was relevant to the viability of three human SS cell lines: Yamato-SS, SYO-1 and HS-SY-II. Next, we assessed the anticancer activity and mechanism of action of TAS-115 in these SS cell lines. Finally, we compared the ability of TAS-115 to inhibit c-MET and PDGFRα phosphorylation with that of pazopanib. Results: We classified the SS cell lines as c-MET-dependent or PDGFRα-dependent based upon the differences in the signalling pathway relevant for growth and/or survival. We also found that c-MET and PDGFRα were the primary activators of both phosphatidylinositol 3-kinase/AKT and mitogen-activated protein kinase pathways in c-MET-dependent and PDGFRα-dependent SS cells, respectively. TAS-115 treatment blocked the phosphorylation of PDGFRα as well as that of c-MET and their downstream effectors, leading to marked growth inhibition in both types of SS cell lines in in vitro and in vivo studies. Furthermore, PDGFRα phosphorylation, on at least four representative autophosphorylation sites, was impeded by TAS-115 equivalently to pazopanib. Conclusions: These experimental results have demonstrated the significance of c-MET and PDGFRα signalling for growth and/or survival of SS tumours. TAS-115 monotherapy may benefit SS patients whose tumours are dependent upon either c-MET or PDGFRα signalling by functioning as a multiple tyrosine kinase inhibitor to suppress c-MET as well as PDGFRα pathways.
Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors
Invest New Drugs 2020 Aug;38(4):1175-1185.PMID:31820255DOI:10.1007/s10637-019-00859-4.
TAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5 days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200-800 mg SID administered to 21 patients), systemic exposure after single administration increased almost dose-proportionally. Three dose-limiting toxicities (DLTs) were observed in three patients: grade 3 rash (650 mg), thrombocytopenia with bleeding, and rash (800 mg). The maximum tolerated dose (MTD) was determined as 650 mg SID. In part 2, the 5-on/2-off schedule was evaluated at the MTD to improve treatment exposure. No DLTs were observed and no patients required treatment interruption in cycle 1. During part 2 and the expansion part (N = 61), grade ≥3 treatment-related adverse events were reported in 47 patients, with neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each), and leukocytopenia (11.5%) occurring in ≥10% of patients. The best overall response was stable disease in 31 of 82 patients (37.8%). An apparent reduction in fluorodesoxyglucose-uptake and bone scan index was observed in some patients. TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed.