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A compound with double inhibitory effects of egfr and wnt, preparation method and application thereof

A technology of inhibition and compound, applied in the direction of organic chemistry, medical preparations containing active ingredients, drug combination, etc., to achieve the effects of strong practical value, easy to achieve large-scale production, and simple preparation method

Active Publication Date: 2022-08-09
SHANGHAI UNIV OF T C M +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far no drugs targeting the Wnt / β-catenin signaling pathway have been used clinically
[0005] In particular, there are currently no reports of dual-targeted drugs that can inhibit both the EGFR signaling pathway and the Wnt signaling pathway

Method used

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  • A compound with double inhibitory effects of egfr and wnt, preparation method and application thereof
  • A compound with double inhibitory effects of egfr and wnt, preparation method and application thereof
  • A compound with double inhibitory effects of egfr and wnt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: Preparation of the compound of formula I (abbreviated as JK11):

[0041]

[0042] At room temperature, the compound of formula II (4-(4-amino-1H-pyrazol-1-yl)-1-tert-butoxycarbonyl-piperidine, 53.3 mg, 0.2 mmol) was first dissolved in DMF (5 ml), 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), the reaction system was mixed uniformly and then stirred at room temperature for 1 hour;

[0043] Finish the reaction, add 0.25ml of 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 to the reaction solution was added the compound of formula IV (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-quinazolin-4-amine hydrochloride, 77.4 mg, 0.18mmol) and a catalyst formed by compounding 0.2ml CuSO4 aqueous solutio...

Embodiment 2

[0048] Example 2: Inhibitory effect of compound of formula I on Wnt / β-catenin pathway

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

[0050] TOP / Flash experimental procedure: 293FT cells were seeded into 96-well white plates (20,000 cells / well), and 24 hours after seeding, they were transfected with TOP / Flash plasmid and Renilla plasmid, and 6 hours later, JK11 (10 μM) was administered. After 24 hours of treatment, detection luciferase activity.

[0051] EPT2-TGC cell validation steps: EPT2 cells stably integrated with the TGC reporter system were seeded in 96-well plates and given 1 μM 6-Bronoindirubin-3'-oxime 12 hours later )...

Embodiment 3

[0057] Example 3: Inhibitory effect of compound of formula I 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 assay: EGFR kinase inhibitory activity was tested using the LANCE Ultra enzyme activity assessment method. Add 2.5 μL of kinase solution to each well according to the arrangement, add 2.5 μL of reaction solution to control wells, add 2.5 μL of compound (JK11 or positive control)) solution to each well according to arrangement, add 2.5 μL of reaction solution to control wells, add 2.5 μL of reaction solution to each well according to arrangement 5μL of base solution, 10μL of Eu-anti-phospho-4E-BP1 and EDTA reaction reagents were added to each well, centrifuged for mixing, and left to equi...

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Abstract

The invention discloses a compound with dual inhibitory effects on EGFR and Wnt, a preparation method and application thereof, and the compound has the chemical structure shown in formula I: the research results show that the compound of formula I in the present invention has an inhibitory effect on EGFR and Wnt. All signaling pathways show significant targeted inhibition, and are expected to be used for the preparation of EGFR inhibitors, Wnt inhibitors or EGFR / Wnt dual inhibitors, especially for the preparation of treatment and / or prevention of EGFR overexpression or / or prevention. And cancer drugs mediated by over-activation of Wnt signaling pathway have medicinal prospects.

Description

technical field [0001] The invention relates to a compound with dual inhibitory effects of EGFR and Wnt, a preparation method and application thereof in antitumor drugs, and belongs to the technical field of chemical drugs. Background technique [0002] Cancer is a disease that endangers human health. The main treatment methods for cancer are surgery, radiotherapy with instruments, and adjuvant chemotherapy with chemotherapy. However, even combining these three methods cannot guarantee a patient's recovery and is prone to recurrence after surgery. With the continuous progress of molecular biotechnology and the deepening of the exploration of the pathogenesis of cancer, people have begun to target cell receptors, key genes and regulatory molecules, which is called molecular targeted therapy (Molecular Targeted therapy). Targeted therapy drugs are all single-targeted drugs, and single-targeted drugs have the disadvantages of narrow adaptability and easy drug resistance. There...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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