Flumatinib mesylate (HHGV-678)

Alias: HHGV678 mesylate; HHGV 678mesylate ; HHGV-678 mesylate; HH-GV-678mesylate
Cat No.:V3406 Purity: ≥98%
Flumatinib mesylate (formerly HHGV678; HHGV-678), the mesylate salt of flumatinib which is first approved 2nd generation TKI in China and an imatinib derivative, is a potent inhibitor of multi-kinase such as c-Abl, PDGFRβ and c-Kit with IC50 values of 1.2 nM, 307.6 nM and 2662 nM, respectively.
Flumatinib mesylate (HHGV-678) Chemical Structure CAS No.: 895519-91-2
Product category: Bcr-Abl
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Flumatinib mesylate (HHGV-678):

  • Flumatinib (HHGV-678)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Flumatinib mesylate (formerly HHGV678; HHGV-678), the mesylate salt of flumatinib which is first approved 2nd generation TKI in China and an imatinib derivative, is a potent inhibitor of multi-kinase such as c-Abl, PDGFRβ and c-Kit with IC50 values of 1.2 nM, 307.6 nM and 2662 nM, respectively. In triplicate, cells (5 × 103) were incubated with different concentrations of imatinib, flumatinib, or sunitinib in 96-well plates for 72 hours, using 200 μL medium containing or lacking IL-3. The cells were incubated for 4 hours after we added MTT. The insoluble purple formazan product was dissolved into a colored solution by adding a solubilization solution, which is a solution of the detergent SDS in diluted hydrochloric acid. A spectrophotometer was used to measure the absorbance of this colored solution at 570 nm using a 650 nm reference filter. The ratio of average absorbance in drug-treated wells to no-drug controls was used to plot growth inhibition. GraphPad Prism version 5, a program for curve-fitting, was used to determine the IC50 values.

Biological Activity I Assay Protocols (From Reference)
Targets
PDGFRβ (IC50 = 307.6 nM); c-Abl (IC50 = 1.2 nM); c-Kit (IC50 = 665.5 nM)
ln Vitro

Flumatinib mesylate (HH-GV-678) (0-1000 μM; 4, 7 and 10 days) inhibits cellular Bcr-Abl autophosphorylation as well as Stat5 and Erk1/2 phosphorylation in K562 leukemia cells[1].
Flumatinib mesylate (HH-GV-678) (0-10 μM; 72 hours) significantly reduces the cell count in chronic myelogenous leukemia cell lines[1].

ln Vivo
Flumatinib mesylate (HH-GV-678) (18-75 mg/kg; p.o.; Twice daily, for 14 days.) inhibits tumor growth in mice that are not clothed
Enzyme Assay
Retroviral constructs based on murine stem cell viruses that carried either activating mutant D816V (816 Asp→Val) KIT cDNA or murine–human hybrid WT KIT cDNA were kindly provided by Michael H. Tomasson (Washington University School of Medicine, St. Louis, MO, USA). The intracellular region of human KIT was fused in-frame with the extracellular and transmembrane regions of murine KIT to create hybrid KIT alleles. It has been demonstrated that substituting homologous murine sequences for the human extracellular and transmembrane domains of KIT can increase the expression efficiency and preserve the capacity to transform some KIT mutants in murine cells. The enhanced GFP cassette from the downstream internal ribosomal entry site causes KIT alleles to coexpress with enhanced GFP. In accordance with Molecular Cloning's third edition of Protocol 3, mutagenesis, the KIT point mutations were produced. Mutagenic primers were created to avoid the deleted sequence in insertion mutagenesis and to harbor the deleted sequence in deletion mutagenesis, respectively. Primestar Hot Start DNA polymerase (Takara, Dalian, China) with high fidelity was used in all of the PCRs mentioned above. Takara was also the source of additional enzymes used in the aforementioned experiments. By using direct sequencing, the sequences of every mutant in this study were confirmed.
Cell Assay
In triplicate, cells (5 × 103) were incubated with different concentrations of imatinib, flumatinib, or sunitinib in 96-well plates for 72 hours, using 200 μL medium containing or lacking IL-3. The cells were incubated for 4 hours after we added MTT. The insoluble purple formazan product was dissolved into a colored solution by adding a solubilization solution, which is a solution of the detergent SDS in diluted hydrochloric acid. A spectrophotometer was used to measure the absorbance of this colored solution at 570 nm using a 650 nm reference filter. The ratio of average absorbance in drug-treated wells to no-drug controls was used to plot growth inhibition. GraphPad Prism version 5, a program for curve-fitting, was used to determine the IC50 values.
Animal Protocol
Nude mice (subcutaneously injecting K562 cells)
18.75, 37.5, 75 mg/kg
Oral administration; Twice daily, for 14 days.
References

[1]. HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance. Leukemia. 2010 Oct;24(10):1807-9.

[2]. Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants. Cancer Sci. 2013 Nov 10.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C₃₀H₃₃F₃N₈O₄S
Molecular Weight
658.69
Exact Mass
658.23
Elemental Analysis
C, 54.70; H, 5.05; F, 8.65; N, 17.01; O, 9.72; S, 4.87
CAS #
895519-91-2
Appearance
Solid powder
SMILES
CC1=C(C=C(C=N1)NC(=O)C2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)NC4=NC=CC(=N4)C5=CN=CC=C5.CS(=O)(=O)O
InChi Key
ZSASDYCFROUKTJ-UHFFFAOYSA-N
InChi Code
InChI=1S/C29H29F3N8O.CH4O3S/c1-19-26(38-28-34-9-7-25(37-28)21-4-3-8-33-16-21)15-23(17-35-19)36-27(41)20-5-6-22(24(14-20)29(30,31)32)18-40-12-10-39(2)11-13-40;1-5(2,3)4/h3-9,14-17H,10-13,18H2,1-2H3,(H,36,41)(H,34,37,38);1H3,(H,2,3,4)
Chemical Name
methanesulfonic acid;4-[(4-methylpiperazin-1-yl)methyl]-N-[6-methyl-5-[(4-pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide
Synonyms
HHGV678 mesylate; HHGV 678mesylate ; HHGV-678 mesylate; HH-GV-678mesylate
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ≥ 32 mg/mL
Water: N/A
Ethanol: N/A
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.5182 mL 7.5908 mL 15.1816 mL
5 mM 0.3036 mL 1.5182 mL 3.0363 mL
10 mM 0.1518 mL 0.7591 mL 1.5182 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04739826 Recruiting Drug: Flumatinib Mesylate
Drug: Nilotinib Pill
CML, Chronic Phase; TKI The First Affiliated Hospital
of Soochow University
September 25, 2020
NCT05367765 Not yet recruiting Drug: Flumatinib
Drug: Imatinib
CML, Chronic Phase Jiangsu Hansoh Pharmaceutical
Co., Ltd.
April 30, 2022 Phase 4
NCT04681820 Recruiting Drug: Flumatinib
Drug: Nilotinib
CML-CP; Mutation;Suboptimal
Response or Failure in TKI
Wuhan Union Hospital, China November 1, 2020
NCT05071482 Recruiting Drug: Flumatinib
Drug: Imatinib
Acute Leukemia wang, jianxiang September 16, 2021 Phase 4
NCT05353205 Recruiting Drug: Flumatinib mesylate tablets
(400mg)
Drug: Flumatinib mesylate tablets
(600mg)
CML, Chronic Phase Jiangsu Hansoh Pharmaceutical
Co., Ltd.
November 23, 2021 Phase 4
Biological Data
  • Flumatinib


    KIT mutants, downstream signaling effectors ERK1/2, and signal transducer and activator of transcription-3 (STAT3), are constitutively phosphorylated in transformed 32D cell lines.2014 Jan;105(1):117-25.

  • Flumatinib


    Effects of imatinib, flumatinib, and sunitinib on the phosphorylation of KIT, ERK1/2, and signal transducer and activator of transcription-3 (STAT3) in 32D-V559D (a) and 32D-V559D+Y823D (b) cells.2014 Jan;105(1):117-25.

  • Flumatinib


    Molecular modeling of the interactions between flumatinib and KIT kinase domain. (a) Structures of imatinib and flumatinib. (b) Molecular docking model of the KIT/flumatinib complex.2014 Jan;105(1):117-25.

  • Flumatinib


    In vivoeffects of imatinib, flumatinib, and sunitinib on the survival of mice after s.c. injection of 32D-V559D (a) or 32D-V559D+Y823D (b) cells.2014 Jan;105(1):117-25.

  • Flumatinib


    Pharmacokinetic (PK) and pharmacodynamic properties of imatinib, flumatinib, and sunitinib. Mice bearing 32D-V559D+Y823D tumors received a single dose of 150mg/kg imatinib, 75mg/kg flumatinib, or 50mg/kg sunitinib.2014 Jan;105(1):117-25.

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