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A novel azaindole-2-one FGFR1 inhibitor and its antitumor activity

A tumor, A116 technology, applied in the chemical structure of azaindol-2-one compounds, anti-tumor applications, can solve the problems of large toxic side effects, inhibitory effects, multi-drug resistance, etc.

Inactive Publication Date: 2017-05-03
WENZHOU MEDICAL UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Most of the current small-molecule inhibitors of FGFR1 are ATP competitive inhibitors. These traditional ATP competitive inhibitors have common disadvantages: 1) Poor specific targeting, large toxic and side effects, and prone to multidrug resistance; 2 ) The inhibitory effect on FGFR1 will be affected by the concentration of ATP in the environment, and it is easy to lose its pharmacological effect in the tissue or cell state with high ATP concentration
[0004] At present, there is no research report on azaindol-2-one FGFR1 non-ATP competitive small molecule compounds. After long-term and arduous research experiments, the inventors designed and synthesized a series of azaindol-2-ones It is found that they have good FGFR1 inhibitory activity in vivo and in vitro and target selectivity through pharmacological activity testing, especially they are non-ATP competitive inhibitors, which can be used to treat various tumors with high FGFR1 expression

Method used

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  • A novel azaindole-2-one FGFR1 inhibitor and its antitumor activity
  • A novel azaindole-2-one FGFR1 inhibitor and its antitumor activity
  • A novel azaindole-2-one FGFR1 inhibitor and its antitumor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 compound inhibits the activity and selectivity of FGFR1 in vitro

[0021] In vitro activity screening of FGFR1 kinase: The method used in the experiment is Caliper Mobility Shift Assay, which is a detection platform based on the mobility detection technology of microfluidic chip technology. Experimental steps: configure 1.25x kinase reaction buffer (62.5mmol / L HEPES, pH7.5; 0.001875% Brij-35; 12.5mmol / LMgCl2; 2.5mM DTT) and kinase reaction termination solution (100mmol / L HEPES, pH7.5 ; 0.015% Brij-35; 0.2% Coating Reagent#3); Add 10 μl of 2.5x FGFR1 kinase solution (in 1.25x kinase reaction buffer add kinase in solution), incubate at room temperature for 10min, then add 10μl of 2.5x substrate peptide solution (add FAM-labeled peptide and ATP in 1.25x kinase reaction buffer), add 25μl kinase reaction after reacting at 28℃ for a specific time stop solution. Test and collect data on Caliper, inhibition rate of kinase activity=(max-conversion) / (max-min)*100. "m...

Embodiment 2

[0024] Antitumor activity verification of compound on the cell level in Example 2

[0025] The compound A116 was formulated into 5, 10 and 20um concentration solutions with DMSO respectively, and the H460 and MRC-5 cells with high expression of FGFR1 were treated with bFGF and bFGF combined with the above-mentioned active compounds at different concentrations, and the anti-tumor proliferation activity of the two compounds was detected At the same time, total cell protein was extracted, and Western blotting was used to detect the changes in the phosphorylation levels of pro-proliferation signal molecules FGFR, ERK and AKT in the bFGF / FGFR signaling pathway in cells. Compound A116 has good anti-tumor proliferation activity, and can strongly inhibit p-FGFR1, p-AKT and p-ERK levels at three concentrations of 5, 10 and 20um (see image 3 ).

Embodiment 3

[0026] Example 3 Non-ATP Competitive Inhibitory Binding Mode of Compound A116 to FGFR1

[0027] Compound A116 was selected, and 10 concentration gradients were configured from 0 to 100 μmol / L using the kinase inhibitory activity screening method, and each concentration was tested in 8 different ATP concentration reaction systems for the conversion of substrate peptides catalyzed by FGFR1 kinase. Influence, the competitive or non-competitive inhibition curves were fitted by software such as GraphPad Prism, and non-ATP competitive enzyme inhibition reaction parameters such as Michaelis constant (Km) and enzymatic maximum reaction rate (Vmax) were calculated at each concentration. Experimental results such as Figure 4 As shown, compared with the standard pd173074, as the concentration of ATP increases, the combination of compound A116 and FGFR1 is not affected by the concentration of ATP, indicating that the inhibitory binding mode of compound A116 and FGFR1 is non-ATP competiti...

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Abstract

The invention provides a novel azaindole-2-ketone FGFR1 (Fibroblast Growth Factor Receptor1) non-ATP (Adenosine Triphosphate) competitive inhibitor with an anti-tumor effect. In addition, the invention also provides a medicine composition of the compound, the anti-tumor application of the compound and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to the chemical structure of azaindol-2-one compounds with antitumor effect. In addition, the present invention also relates to the FGFR1 non-ATP competitive inhibition mechanism and anti-tumor application of the compound. Background technique [0002] Fibroblast Growth Factor receptor (FGFR) is a receptor-type protein tyrosine kinase involved in the regulation of cell proliferation, apoptosis, angiogenesis, migration and invasion. Currently known FGFR mainly includes four types, namely FGFR1, FGFR2, FGFR3 and FGFR4, among which FGFR1 is most closely related to tumors. As an important target of anti-tumor drugs, the research and development of small molecule inhibitors of FGFR1 has received more and more attention. At present, no FGFR1 inhibitors have entered clinical use. Therefore, a new type of FGFR1 small molecule inhibitors with my country's independen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/496A61P35/00
CPCC07D471/04
Inventor 刘志国赵云洁陈高帜冯建鹏王怡俞鹏天梁广
Owner WENZHOU MEDICAL UNIV
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