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Preparation of two novel non-ATP (Adenosine Triphosphate) competitive FGFR1 (Fibroblast Growth Factor Receptor1) inhibitors and anti-tumor activity of two novel non-ATP competitive FGFR1 inhibitors

A tumor and tumor-related technology, applied in the fields of anti-tumor drugs, organic chemistry, drug combination, etc., can solve the problems of loss of pharmacological effects, influence, and large toxic and side effects.

Inactive Publication Date: 2013-07-24
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The current small molecule inhibitors of FGFR are all ATP competitive inhibitors, and these traditional ATP competitive inhibitors have common disadvantages: 1) Poor specific targeting, large toxic and side effects, and easy to produce 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 the pharmacological effect in the tissue or cell state with high ATP concentration
[0004] At present, there is no research report on acrylamide FGFR1 non-ATP competitive small molecule compounds. After long-term and arduous research experiments, the inventors designed and synthesized a series of bisaryl-1,4-dien-3-ketones It is found that they have good inhibitory activity and target selectivity of FGFR1 in vivo and in vitro, especially they are non-ATP competitive inhibitors, and can be used to treat various tumors with high expression of FGFR1

Method used

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  • Preparation of two novel non-ATP (Adenosine Triphosphate) competitive FGFR1 (Fibroblast Growth Factor Receptor1) inhibitors and anti-tumor activity of two novel non-ATP competitive FGFR1 inhibitors
  • Preparation of two novel non-ATP (Adenosine Triphosphate) competitive FGFR1 (Fibroblast Growth Factor Receptor1) inhibitors and anti-tumor activity of two novel non-ATP competitive FGFR1 inhibitors
  • Preparation of two novel non-ATP (Adenosine Triphosphate) competitive FGFR1 (Fibroblast Growth Factor Receptor1) inhibitors and anti-tumor activity of two novel non-ATP competitive FGFR1 inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation of embodiment 1 compound A114, A117:

[0025] Preparation of intermediate thiophene-2-acrylic acid: Add 0.024mol (2.50g) malonic acid, 0.02mol thiophene-2-carbaldehyde and 0.048mol (3.80g) dry pyridine in a 100ml round bottom flask, then add 0.0005 mol (0.047g) aniline, the mixture was heated to reflux at about 95°C, and the reaction process was monitored by TLC. After the reaction of the raw materials was completed, the reaction was terminated. After cooling, 3mol / L aqueous HCl solution was added dropwise to the system until no solids were produced, filtered, Wash with ice water until the filtrate is neutral, recrystallize and dry to obtain thiophene-2-acrylic acid.

[0026] Preparation of compound (E)-N-(1Hindole-6)-(thiophene-2)-acrylamide (A114): Dissolve 0.11g (0.86mmol) of 5-aminoindole in an appropriate amount of In tetrahydrofuran, after stirring for 5min, add 0.16g (0.16mmol) triethylamine dropwise to the system, after 10min, add 0.13g (0.78mmo...

Embodiment 2

[0030] Example 2 Compound Inhibits FGFR1 Activity and Selectivity in Vitro

[0031]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); in 5 μl of 5x concentration compound solution (dissolved in DMSO, diluted 10 times with water), 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...

Embodiment 3

[0034] Antitumor Activity Verification of Compounds at the Cell Level in Example 3

[0035] Compound A114 and compound A117 were formulated into 5, 10 and 20um concentration solutions with DMSO, respectively, and bFGF and bFGF combined with the above-mentioned different concentrations of active compounds were used to treat H460 and MRC-5 cells with high FGFR1 expression, and the anti-inflammatory effects of the two compounds were detected. Tumor proliferation activity; at the same time, total cell protein was extracted, and Western blotting was used to detect the changes in the phosphorylation levels of the pro-proliferation signal molecules FGFR, ERK and AKT in the bFGF / FGFR signaling pathway in the cells. Both compounds have 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 ).

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Abstract

The invention provides FGFR1 (Fibroblast Growth Factor Receptor1) non-ATP (Adenosine Triphosphate) competitive inhibitor acrylamide compounds. Besides, the invention also provides a medicine composite of the compounds, anti-tumor application of the compounds, and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to acrylamide compounds with antitumor effect. In addition, the present invention also relates to the FGFR non-ATP competitive inhibition mechanism of these two compounds and their anti-tumor applications. Background technique [0002] Fibroblast growth factor receptor (FGFR) is a type of membrane-penetrating receptor tyrosine kinase, and currently known FGFR mainly includes four types, namely FGFR1, FGFR2, FGFR3 and FGFR4. Receptor tyrosine kinases play an important role in the signaling pathways that control cell proliferation and differentiation. Mutations or abnormally high expression of protein kinases will lead to abnormal enhancement of kinase activity, which has been proven to be related to the occurrence of various cancers. Most tumor cells (breast cancer, pancreatic cancer, astrocytoma, salivary gland cancer, Kaposi's sarcoma, ovarian cancer and p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12A61K31/404A61K31/4184A61P35/00
Inventor 李雪琳朱和平梁广刘志国胡杰陈高帜蔡跃飘王怡
Owner WENZHOU MEDICAL UNIV
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