Compound with EGFR and Wnt dual inhibition effects and preparation method and application thereof

A technology of inhibition and compounds, applied in organic chemistry, medical preparations containing active ingredients, drug combinations, etc., to achieve strong practical value, easy to achieve large-scale production, and simple preparation methods

Active Publication Date: 2021-09-28
SHANGHAI UNIV OF T C M +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, so far no drugs targeting the Wnt/β-catenin signaling pathway have been used clinically
[0005] In particular, there a

Method used

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  • Compound with EGFR and Wnt dual inhibition effects and preparation method and application thereof
  • Compound with EGFR and Wnt dual inhibition effects and preparation method and application thereof
  • Compound with EGFR and Wnt dual inhibition effects and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the preparation of formula I compound (abbreviated as JK11):

[0041]

[0042] At room temperature, the compound of formula II (4-(4-amino-1H-pyrazol-1-yl)-1-tert-butoxycarbonyl-piperidine, 53.3mg, 0.2mmol) was dissolved in DMF (5ml), Then add potassium bicarbonate aqueous solution (3mol / L, 0.53ml, 1.6mmol) and FSO 2 N 3 (Fluorosulfonyl azide) in methyl tert-butyl ether solution (0.4mol / L, 2.2ml, 0.44mmol), mix the reaction system uniformly and then stir and react at room temperature for 1 hour;

[0043] End the reaction, add 0.25ml sodium ascorbate aqueous solution (0.5mol / L, 0.125mmol) to the reaction system to quench the reaction, to obtain a reaction solution containing the compound of formula III;

[0044] Then, the compound of formula IV (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-quinazolin-4-amine hydrochloride, 77.4 mg, was added to the reaction solution. 0.18mmol) and the catalyst formed by compounding 0.2ml CuSO4 aqueous solution (0.1mol...

Embodiment 2

[0048] Embodiment 2: the inhibitory effect of formula I compound on Wnt / β-catenin pathway

[0049] Experimental materials: 293FT cells were purchased from the Cell Bank of the Chinese Academy of Sciences; EPT2 cells stably integrated with the TGC reporter system were from the University of Bergen, Norway; HCT116 cells were purchased from the Cell Bank of the Chinese Academy of Sciences; SW480 cells were purchased from ATCC; AB zebrafish were purchased from the National Zebra Fish Resource Center.

[0050] TOP / Flash experimental procedure: 293FT cells were inoculated into 96-well white plate (20,000 cells / well). After 24 hours, the plate was given transfection TOP / Flash plasmid and Renilla plasmid. After 6 hours, JK11 (10 μ M) was given. After 24 hours of treatment, the Luciferase activity.

[0051] EPT2-TGC cell verification steps: Inoculate EPT2 cells with a stably integrated TGC reporter system in a 96-well plate, and give 1 μM 6-bromoindirubin-3'-oxime (6-Bronoindirubin-3'...

Embodiment 3

[0057] Embodiment 3: the inhibitory effect of formula I compound on EGFR

[0058] Experimental materials: A549 cells were purchased from the Cell Bank of the Chinese Academy of Sciences; A549 cells were purchased from the Cell Bank of the Chinese Academy of Sciences; P-EGFR, EGFR and GAPDH antibodies were purchased from CST; the control drug Erlotinib was purchased from Sigma.

[0059] EGFR kinase detection: EGFR kinase inhibitory activity was tested by LANCE Ultra enzyme activity evaluation method. Add 2.5 μL kinase solution to each well according to the arrangement, add 2.5 μL reaction solution to the control well, add 2.5 μL compound (JK11 or positive control)) solution to each well according to the arrangement, add 2.5 μL reaction solution to the control well, add Add 10 μL of Eu-anti-phospho-4E-BP1 and EDTA reaction reagent to 5 μL of substrate solution, centrifuge for mixing, and place it at room temperature for 60 minutes. The final concentration of Eu-anti-phospho-4E-B...

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Abstract

The invention discloses a compound with EGFR and Wnt dual inhibition effects and a preparation method and application thereof. The compound has a chemical structure as shown in a formula I. Research results show that the compound as shown in the formula I has a remarkable targeted inhibition effect on EGFR and Wnt signal channels; the compound is expected to be used for preparing an EGFR inhibitor, a Wnt inhibitor or an EGFR/Wnt dual inhibitor, is especially expected to be used for preparing a medicine for treating and/or preventing cancer mediated by EGFR overexpression or/and Wnt signaling pathway overexpression, and has a medicinal prospect.

Description

technical field [0001] The invention relates to a compound with dual inhibitory effects on EGFR and Wnt, its preparation method and its application in antitumor drugs, belonging to the technical field of chemical medicines. Background technique [0002] Cancer is a disease that endangers human health. The main treatment methods for cancer are surgery, radiotherapy with the help of equipment, and adjuvant chemotherapy with chemical drugs. However, even combining these three methods cannot guarantee the patient's recovery, and it is easy to relapse after surgery. With the continuous advancement of molecular biotechnology and the in-depth exploration of the pathogenesis of cancer, people began to target cell receptors, key genes and regulatory molecules, called molecular targeted therapy (Molecular Targeted therapy), but At present, targeted therapy drugs are all single-targeted drugs, and single-targeted drugs have the disadvantages of narrow adaptability and easy drug resist...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00A61K31/517
CPCC07D401/14A61P35/00
Inventor 柯细松董佳家闫蓉马天成屈祎黄飄
Owner SHANGHAI UNIV OF T C M
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