Flumatinib (HHGV678)
(Synonyms: 4-[(4-甲基-1-哌嗪基)甲基]-N-[6-甲基-5-[[4-(3-吡啶基)-2-嘧啶基]氨基]-3-吡啶基]-3-(三氟甲基)苯甲酰胺,HHGV678) 目录号 : GC32867
A Bcr-Abl inhibitor
Cas No.:895519-90-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Flumatinib is an inhibitor of the non-receptor tyrosine kinase Bcr-Abl (IC50 = 1.2 nM).1 It is selective for Bcr-Abl over VEGFR2, c-Src, EGFR, and HER2 at 1 ?M but does inhibit PDGFRβ and c-Kit (IC50s = 307.6 and 665.5 nM, respectively). Flumatinib inhibits the proliferation of K562 chronic myelogenous leukemia (CML) cells expressing wild-type Bcr-Abl (IC50 = 5.1 nM) and 32D cells expressing the Bcr-Abl mutations Bcr-AblQ252H, Bcr-AblY253F, Bcr-AblE255K, Bcr-AblM351T, and Bcr-AblH396P (IC50s = 76.3, 40.4, 123.2, 20.2, and 34.6 nM, respectively), which confer resistance to the c-Abl, Bcr-Abl, PDGFR, and c-Kit inhibitor imatinib . It also induces tumor regression and increases survival time in a K562 mouse xenograft model when administered at a dose of 75 mg/kg per day. Flumatinib also increases the viability of Vero E6 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; EC50 = 1.6 ?M) and reduces the levels of SARS-CoV-2 in the supernatant of Vero E6 infected cells.2
1.Luo, H., Quan, H., Xie, C., et al.HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistanceLeukemia24(10)1807-1809(2010) 2.Singh, A., and Arkin, I.T.Targeting viral ion channels: A promising strategy to curb SARS-CoV-2Pharmaceuticals (Basel)15(4)396(2022)
| Cas No. | 895519-90-1 | SDF | |
| 别名 | 4-[(4-甲基-1-哌嗪基)甲基]-N-[6-甲基-5-[[4-(3-吡啶基)-2-嘧啶基]氨基]-3-吡啶基]-3-(三氟甲基)苯甲酰胺,HHGV678 | ||
| Canonical SMILES | O=C(NC1=CC(NC2=NC=CC(C3=CC=CN=C3)=N2)=C(C)N=C1)C4=CC=C(CN5CCN(C)CC5)C(C(F)(F)F)=C4 | ||
| 分子式 | C29H29F3N8O | 分子量 | 562.59 |
| 溶解度 | DMSO : ≥ 32 mg/mL (56.88 mM) | 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 | 1.7775 mL | 8.8875 mL | 17.7749 mL |
| 5 mM | 0.3555 mL | 1.7775 mL | 3.555 mL |
| 10 mM | 0.1777 mL | 0.8887 mL | 1.7775 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。
Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase III, Randomized, Open-label, Multi-center FESTnd Study
Clin Cancer Res 2021 Jan 1;27(1):70-77.PMID:32928796DOI:10.1158/1078-0432.CCR-20-1600.
Purpose: Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. We evaluated the efficacy and safety of Flumatinib versus imatinib, for first-line treatment of chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (CML-CP). Patients and methods: In this study, 394 patients were randomized 1:1 to Flumatinib 600 mg once daily (n = 196) or imatinib 400 mg once daily (n = 198) groups. Results: The rate of major molecular response (MMR) at 6 months (primary endpoint) was significantly higher with Flumatinib than with imatinib (33.7% vs. 18.3%; P = 0.0006), as was the rate of MMR at 12 months (52.6% vs. 39.6%; P = 0.0102). At 3 months, the rate of early molecular response (EMR) was significantly higher in patients receiving Flumatinib than in those receiving imatinib (82.1% vs. 53.3%; P < 0.0001). Compared with patients receiving imatinib, more patients receiving Flumatinib achieved molecular remission 4 (MR4) at 6, 9, and 12 months (8.7% vs. 3.6%, P = 0.0358; 16.8% vs. 5.1%, P = 0.0002; and 23.0% vs. 11.7%, P = 0.0034, respectively). No patients had progression to accelerated phase or blast crisis in the Flumatinib arm versus 4 patients in the imatinib arm by 12 months. Adverse events of edema, pain in extremities, rash, neutropenia, anemia, and hypophosphatemia were more frequent in imatinib arm, whereas diarrhea and alanine transaminase elevation were more frequent in Flumatinib arm. Conclusions: Patients receiving Flumatinib achieved significantly higher rates of responses, and faster and deeper responses compared with those receiving imatinib, indicating that Flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644.See related commentary by Müller, p. 3.
Metabolic interactions between Flumatinib and the CYP3A4 inhibitors erythromycin, cyclosporine, and voriconazole
Pharmazie 2020 Sep 1;75(9):424-429.PMID:32797767DOI:10.1691/ph.2020.0068.
Flumatinib, indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, is a structural analog of imatinib and has shown higher potency than imatinib as a BCR-ABL inhibitor. In this paper, the metabolic profile of Flumatinib was studied. It was found that CYP3A4 and CYP2C8 were the main cytochrome P450 enzyme substyles catalyzing the metabolism of Flumatinib, and CYP3A4 has a stronger metabolic ability for Flumatinib than CYP2C8. Erythromycin, cyclosporine, and voriconazole can inhibit the metabolism of Flumatinib in vitro. Accordingly, co-administration of erythromycin and cyclosporine with Flumatinib increased the plasma concentration and the systemic exposure of Flumatinib in rats, which indicated that lower doses should be considered in clinical practice.
Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants
Cancer Sci 2014 Jan;105(1):117-25.PMID:24205792DOI:10.1111/cas.12320.
Activating mutations in KIT have been associated with gastrointestinal stromal tumors (GISTs). The tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GISTs. Unfortunately, primary or acquired resistance to imatinib does occur in GISTs and forms a major problem. Although sunitinib malate, a multi-kinase inhibitor, has shown effectiveness against imatinib-resistant GISTs, recent studies have indicated that some imatinib-resistant GISTs harboring secondary mutations in the KIT activation loop were also resistant to sunitinib. Therefore, new drugs capable of overcoming the dual drug resistance of GISTs probably have potential clinical utility. In this study, we investigated the efficacy of Flumatinib, an inhibitor of BCR-ABL/PDGFR/KIT, against 32D cells transformed by various KIT mutants and evaluated its potency to overcome the drug resistance of certain mutants. Interestingly, our in vitro study revealed that Flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P). Our in vivo study consistently suggested that Flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D. Molecular modeling of Flumatinib docked to the KIT kinase domain suggested a special mechanism underlying the capability of Flumatinib to overcome the drug-resistance conferred by activation loop mutations. These findings suggest that Flumatinib could be a promising therapeutic agent against GISTs resistant to both imatinib and sunitinib because of secondary mutations in the activation loop.
[Effect of Flumatinib mesylate on C-MYC, HIF-1α and VEGF in U226 line]
Zhongguo Shi Yan Xue Ye Xue Za Zhi 2013 Dec;21(6):1496-500.PMID:24370036DOI:10.7534/j.issn.1009-2137.2013.06.024.
The objective of this study was to investigate the effect of the new generation of tyrosine kinase inhibitor Flumatinib mesylate on C-MYC, HIF-1α and VEGF in multiple myeloma (MM) cell line U266. Different concentrations (1, 5, 10 µmol/L) of Flumatinib mesylate were used to act on U266 cell line for 8, 16 and 24 h, and the expression of C-MYC, and HIF-1α genes was detected by real-time fluorescence-quantitative PCR, the expression of C-MYC, HIF-1α and VEGF was measured by Western blot. The results showed that the gene expression of C-MYC and HIF-1 genes decreased gradually with the increasing of Flumatinib mesylate concentration (P < 0.05). At the same concentration of Flumatinib mesylate, the expression of C-MYC and HIF-1α gene decreased gradually with prolonging of treatment time with the Flumatinib mesylate (P < 0.05). When the Flumatinib mesylate acted the U266 cell line for 16 h, the expression of C-MYC, HIF-1α and VEGF decreased gradually with the increasing of Flumatinib mesylate concentration (P < 0.05). It is concluded that the Flumatinib mesylate can reduce the expression of C-MYC, HIF-1 α and VEGF in U266 cell line in a time- and dose-dependent manners, so Flumatinib mesylate may become a new drug for MM therapy.
Effect of high-fat diet on the pharmacokinetics and safety of Flumatinib in healthy Chinese subjects
Cancer Chemother Pharmacol 2020 Sep;86(3):339-346.PMID:32757049DOI:10.1007/s00280-020-04117-w.
Purpose: To evaluate the effect of a high-fat diet on the pharmacokinetics and safety of Flumatinib mesylate tablets in healthy Chinese subjects. Methods: This study was a randomized, open-label, single-dose, two-period crossover trial in which subjects were randomly assigned to take 400 mg of Flumatinib mesylate after a high-fat diet or a fasted state. After a 14-day washout period, the two groups were administered Flumatinib mesylate under opposite conditions. Blood samples were collected at baseline 0 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h, respectively. Plasma concentrations of Flumatinib and its metabolites (M1 and M3) were analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using the non-compartmental module of the Phoenix WinNonlin Version 7.0 software. BE module of WinNonLin was used for statistical analysis of AUC0-t, AUC0-∞ and Cmax in plasma. Results: Twelve healthy subjects, half male and half female, were enrolled. One subject withdrew due to a treatment-emergent adverse event. Eleven subjects were administered drugs on fasting and 12 were administered drugs after a high-fat diet. On high-fat diet/fasting, the least square geometric mean (LSGM) ratios of Flumatinib, M1, M3, and their 90% confidence interval (CI) were as follows: for Flumatinib, Cmax, AUC0-t and AUC0-∞ were 281.65% (225.80-351.31%), 167.43% (143.92-194.79%), and 166.87% (143.47-194.09%); for M1, Cmax, AUC0-t, and AUC0-∞ were 188.59% (145.29-244.79), 163.94% (149.11-180.24%), and 164.48% (150.36-179.94%); for M3, Cmax, AUC0-t, and AUC0-∞ were 63.47% (54.02-74.57%), 85.23% (74.72-97.22%), and 96.73% (86.63-108.02%). Conclusion: Among the subjects, oral administration of 400 mg of Flumatinib was safe and well tolerated. High-fat diet significantly increases the exposure to Flumatinib, therefore, fasting may be recommended. Clinical trial registration: The study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.