BMS-777607
(Synonyms: N-[4-[(2-氨基-3-氯吡啶-4-基)氧基]-3-氟苯基]-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺,BMS 817378) 目录号 : GC14214
BMS-777607 是一种泛 TAM 抑制剂，对不同类型的癌症显示出抗肿瘤活性。
Cas No.:1025720-94-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
CCA cell lines HuCCT1, KKU-100 |
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Preparation Method |
The HuCCT1 cells were cultured in RPMI-1640 medium. The KKU-100 cells were cultured in DMEM. All the cells were supplemented with 10% heat-inactivated FBS, 100 μg/ml streptomycin, 100 μg/ml penicillin, and 2 mM L glutamine in a humidified atmosphere containing 5% CO2 at 37˚C. |
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Reaction Conditions |
Clonogenic assays were used to measure the growth of the HuCCT1 and KKU-100 cell lines, in the presence of varying concentrations of BMS 777607(1/3/5/10 μM). |
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Applications |
BMS-777607 showed a concentration-dependent antiproliferative effect on both the HuCCT1 and KKU-100 cell lines. Moreover, in HuCCT1 and KKU-100 cell lines, IC50 values after treatment with BMS-777607 for 6 days were 11.4 and 5.9 μM, respectively. In addition, the expression of phospho-RON was decreased in both HuCCT1 and KKU-100 cell lines after treatment with BMS-777607. |
| Animal experiment [1]: | |
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Animal models |
adult male Sprague Dawley (SD) rats (310±14 g) |
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Preparation Method |
The rats were administered 300 mg/l thioacetamide (TAA) via drinking water daily for up to 20 weeks. The gemcitabine/Oxaliplat -in treatment group received gemcitabine [50 mg/kg, intraperitoneal injection(i.p.)] and oxaliplatin (2 mg/kg, i.p.) once every 2 weeks over a 4-week period starting at the 21st week. The BMS-777607 treatment group received BMS-777607 [30 mg/kg, per os (p.o.)] 5 days/week starting at the 21st week. The control group rats received i.p. injections of PBS following the same schedule. |
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Dosage form |
30 mg/kg, per os (p.o.) |
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Applications |
BMS-777607 could significantly suppress the in vivo growth of CCA tumors in animal model. |
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References: [1]. Cheng CT, et al. MET-RON dual inhibitor, BMS-777607, suppresses cholangiocarcinoma cell growth, and MET-RON upregulation indicates worse prognosis for intra-hepatic cholangiocarcinoma patients. Oncol Rep. 2018 Sep;40(3):1411-1421. |
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BMS-777607 is a pan-TAM inhibitor, which shows anti-tumor activity to different types of cancer. BMS-777607 could also enhance the expression of proinflammatory cytokines and pro-immune cells over control with the combination anti-PD-1 treatment. The addition of BMS-777607 to anti- PD-1 treatment down-regulated immunosuppressive cytokines expression in tumor microenvironment. It has been reported that the combined treatment of BMS-777607 with anti-PD-1significantly decreased tumor growth and incidence of lung metastasis [1]
In vitro and in vivo experiment demonstrate that BMS-777607 could inhibit the growth of human CCA cells and decrease the expression of phospho-RON. Moreover, in HuCCT1 and KKU-100 cell lines, IC50 values after treatment with BMS-777607 for 6 days were 11.4 and 5.9 μM, respectively. BMS-777607 could also inhibit the in vivo growth of CCA in rats. [2]
References:
[1].Kasikara C, et al. Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti-PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer. Cancer Res. 2019 May 15;79(10):2669-2683.
[2].Cheng CT, et al. MET-RON dual inhibitor, BMS-777607, suppresses cholangiocarcinoma cell growth, and MET-RON upregulation indicates worse prognosis for intra-hepatic cholangiocarcinoma patients. Oncol Rep. 2018 Sep;40(3):1411-1421.
BMS-777607 是一种泛 TAM 抑制剂，对不同类型的癌症显示出抗肿瘤活性。 BMS-777607 还可以通过联合抗 PD-1 治疗增强促炎细胞因子和促免疫细胞的表达。在抗 PD-1 治疗中加入 BMS-777607 可下调肿瘤微环境中的免疫抑制细胞因子表达。据报道，BMS-777607 与抗 PD-1 联合治疗可显着降低肿瘤生长和肺转移发生率[1]
体外和体内实验表明，BMS-777607 可以抑制人 CCA 细胞的生长并降低磷酸化 RON 的表达。此外，在 HuCCT1 和 KKU-100 细胞系中，用 BMS-777607 处理 6 天后的 IC50 值分别为 11.4 和 5.9 μM。 BMS-777607 还可以抑制大鼠体内 CCA 的生长。 [2]
| Cas No. | 1025720-94-8 | SDF | |
| 别名 | N-[4-[(2-氨基-3-氯吡啶-4-基)氧基]-3-氟苯基]-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺,BMS 817378 | ||
| 化学名 | N-[4-(2-amino-3-chloropyridin-4-yl)oxy-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide | ||
| Canonical SMILES | CCOC1=C(C(=O)N(C=C1)C2=CC=C(C=C2)F)C(=O)NC3=CC(=C(C=C3)OC4=C(C(=NC=C4)N)Cl)F | ||
| 分子式 | C25H19ClF2N4O4 | 分子量 | 512.89 |
| 溶解度 | ≥ 25.65mg/mL 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9497 mL | 9.7487 mL | 19.4974 mL |
| 5 mM | 0.3899 mL | 1.9497 mL | 3.8995 mL |
| 10 mM | 0.195 mL | 0.9749 mL | 1.9497 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。
BMS-777607 promotes megakaryocytic differentiation and induces polyploidization in the CHRF-288-11 cells
Introduction of a polyploidy inducer is a promising strategy to achieve a high level of polyploidization during megakaryocytic (MK) differentiation. Here, we report that a multi-kinase inhibitor, BMS-777607, is a potent polyploidy inducer for elevating high ploidy cell formation in the MK-differentiated CHRF-288-11 (CHRF) cells. Our result showed that BMS-777607 strongly inhibited cell division without affecting cell viability when detected at day 1 after treatment. As a consequence, the high ploidy (≡8N) cells were accumulated in culture for 8 days, with an increase from 16.2 to 75.2 % of the total cell population. The elevated polyploidization was accompanied by the increased expression level of MK marker, CD41 (platelet glycoprotein IIb/IIIa, GPIIb/IIIa), suggesting that BMS-777607 promoted both polyploidization and commitment of MK-differentiated CHRF cells. Platelet-like fragments (PFs) were released by mature CHRF cells. Based on a flow cytometry assay, it was found that the PFs produced from BMS-777607-treated cells tended to have larger size and higher expression of GPIIb/IIIa, a receptor for platelet adhesion. Taken together, these results suggested that BMS-777607 promoted MK differentiation of CHRF cells and increased the functional property of platelet-like fragments.
Antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET
Objective: Tyrosine-protein kinase MET (c-MET) has been reported to be a prognostic marker and suitable therapeutic target for ovarian cancer. BMS-777607, a small molecule, can inhibit MET and other protein kinase activities. The present study was conducted to investigate the mechanism of action and antitumor effect of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.
Materials and methods: Ovarian cancer cells with constitutively activated c-MET were first identified through Western blot analysis. Bio-behaviors, including signal transduction, proliferation, apoptosis, and migration, of the cells with constitutively activated c-MET were evaluated after BMS-777607 treatment. Liu's stain and immunological staining of 汐-tubuline were performed to evaluate the ploidy of the cells. A xenograft mouse model was also used to evaluate the antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.
Results: BMS-777607 could induce the highest inhibition of cell growth in ovarian cancer cells constitutively expressing c-MET. Treating SKOV3 cells with BMS-777607 could reduce c-MET activation and inhibit downstream cell signaling, thus causing cell apoptosis and polyploidy as well as cell cycle and cell migration inhibition. This molecule also inhibited tumor growth in a mouse xenograft model of SKOV3 ovarian cancer cells in vivo.
Conclusion: BMS-777607 exhibits antitumor effects on ovarian cancer cells that constitutively express c-MET through c-MET signaling blockade and the inhibition of Aurora B activity. Combination treatments to enhance the effects of BMS-777607 warrant investigation in the future.
Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents
The RON receptor tyrosine kinase is a therapeutic target for cancer treatment. Here, we report therapeutic effect and phenotypic change of breast cancer cells in response to BMS-777607, a RON tyrosine kinase inhibitor. Treatment of breast cancer cells with BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly, BMS-777607 induced extensive polyploidy with multiple sets of chromosomes in cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific siRNA did not prevent polyploid formation. Immunofluorescent analysis of 汐-tubulin and 污-tubulin expression in polyploid cells revealed that BMS-777607 disrupts bipolar spindle formation and causes multipolar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing kinase-inhibitory profiles, aurora kinase B was identified as the target molecule inhibited by BMS-777607. In BMS-777607-treated cells, aurora kinase B was inhibited followed by protein degradation. Moreover, BMS-777607 inhibited Ser10 phosphorylation of histone H3, a substrate of aurora kinase B. Chemosensitivity analysis indicated the resistance of polyploid cells toward chemotherapeutics. Treatment with doxorubicin, bleomycin, methotrexate, and paclitaxel significantly increased cellular IC50 values. These findings highlight the theory that BMS-777607 acts as a multikinase inhibitor at therapeutic doses and is capable of inducing polyploidy by inhibiting aurora kinase B. Increased resistance of polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted cancer therapy using BMS-777607.
[Effect of Met kinase inhibitor BMS-777607 on proliferation and apoptosis of tongue cell line CAL 27 squamous cell carcinoma]
Purpose: To investigate the effect of Met kinase inhibitor BMS-777607 on proliferation and apoptosis of tongue squamous cell carcinoma cell line CAL27.
Methods: The effect of BMS-777607 on proliferation of CAL27 was detected by MTT method, clone formation assay and EdU cell imaging. Morphological changes of apoptosis of CAL27 cells induced by BMS-777607 were observed by Heochst33342 staining. JC-1 staining was used to detect the changes of mitochondrial membrane potential of CAL27 cells treated with BMS-777607. Western blot was used to detect the effect of BMS-777607 on the expression of proliferation protein Akt, p-Akt and apoptosis-related proteins Bcl-2, Cleaved caspase-3, Bax and Parp in CAL27 cells. The data were analyzed using SPSS 22.0 software package.
Results: BMS-777607 inhibited proliferation and promoted apoptosis of CAL27 cells in a concentration-dependent mannerㄗPˉ0.05ㄘ. It also inhibited the expression of Bcl-2 and p-Akt and promoted the expression of Bax, Cleaved caspase-3 and Parp protein (Pˉ0.05).
Conclusions: BMS-777607 can inhibit proliferation and promote apoptosis of CAL27 cells.
Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics
Targeted inhibition of MET/RON signaling by tyrosine kinase inhibitor BMS-777607 for cancer treatment is currently under clinical trials. We have previously shown that BMS-777607 induces chemoresistance in vitro by causing polyploidy, which hampers therapeutic efficacy. Here, we studied polyploidy-associated senescence induced by BMS-777607 in breast cancer cells and its prevention by mTOR inhibitor AZD8055, leading to increased chemosensitivity. In breast cancer T-47D and ZR-75-1 cells, BMS-777607 induced phenotypic changes including enlarged cellular size, flattened morphology, increased DNA content, and activity of senescence-associated 汕-galactosidase. These changes were accompanied by increased p21/WAF1 expression and decreased Retinoblastoma Ser(780) phosphorylation, indicating that BMS-777607 induces not only polyploidy but also senescence. The appearance of senescence was associated with polyploidy in which 汕-galactosidase is exclusively expressed in polyploid cells. Survivin expression was increased in polyploid/senescent cells as analyzed by Western blotting. Increased survivin accumulated both in the nucleus and cytoplasm and dissociated with condensed DNA and mitotic spindle at the metaphase. Abnormal accumulation of survivin also rendered polyploid/senescent cells insensitive to cytotoxic activities of YM155, a DNA damaging agent with a suppressive effect on survivin gene transcription. AZD8055, a specific mTOR inhibitor, effectively prevented BMS-777607-induced polyploidy and senescence and restored survivin expression and its nuclear localization to normal levels. Although a synergism was not observed, BMS-777607 plus AZD8055 increased cancer cell sensitivity toward different cytotoxic chemotherapeutics. In conclusion, BMS-777607-induced chemoresistance is associated with cell polyploidy and senescence. Inhibition of mTOR signaling by AZD8055 prevents BMS-777607-induced polyploidy/senescence and increases breast cancer cell chemosensitivity.