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Targeting chimera for degrading ERK1/2 protein and application thereof

A chimera and targeting technology, applied in drug combinations, peptide preparation methods, peptides, etc., to achieve good application prospects, inhibit tumor growth, and solve clinical problems

Pending Publication Date: 2022-05-06
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of this application is to provide a targeted chimera for degrading ERK1 / 2 protein and its application, aiming to solve the technical problem of how to better degrade ERK1 / 2 protein

Method used

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  • Targeting chimera for degrading ERK1/2 protein and application thereof
  • Targeting chimera for degrading ERK1/2 protein and application thereof
  • Targeting chimera for degrading ERK1/2 protein and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] A targeting chimera (represented by LB-Pi-A12-TH), whose structure is as follows figure 1 As shown in A, its ERK1 / 2 degradation effect is verified by experiments:

[0096] (1) in 6-well plate with 5×10 5 The density of granule cells / well was planted into PC9 non-small cell lung cancer cell line respectively, and treated with different concentrations of LB-Pi-A12-TH (0, 0.1, 0.3, 1, 3, 10 μM) for 6 hours, or 1 μM Different time points (0, 1, 3, 6, 12, 24 hours).

[0097] (2) After the cells adhere to the wall, add LB-Pi-A12-TH to start the treatment.

[0098] (3) The total protein was collected from the lysate, and after quantification, the expression levels of total ERK and phosphorylated RSK were detected by Western Blot.

[0099] Result analysis: Test results such as figure 1 As shown in B, by Western Blot analysis, LB-Pi-A12-TH treatment can effectively promote the degradation of ERK1 / 2 and the decrease of RSK phosphorylation level as the concentration increase...

Embodiment 2

[0101] A targeting chimera (represented by LB-Pi-A13-TH), whose structure is as follows figure 2 As shown in A, its ERK1 / 2 degradation effect is verified by experiments:

[0102] (1) in 6-well plate with 5×10 5 The density of granule cells / well was planted into PC9 non-small cell lung cancer cell line respectively, and treated with different concentrations of LB-Pi-A14-TH (0, 0.1, 0.3, 1, 3, 10 μM) for 6 hours, or 1 μM Different time points (0, 1, 3, 6, 12, 24 hours).

[0103] (2) After the cells adhered to the wall, LB-Pi-A13-TH was added to start the treatment.

[0104] (3) The total protein was collected from the lysate, and after quantification, the expression levels of total ERK and phosphorylated RSK were detected by Western Blot.

[0105] Result analysis: Test results such as figure 2As shown in B, by Western Blot analysis, LB-Pi-A13-TH treatment can effectively promote the degradation of ERK1 / 2 and the decrease of RSK phosphorylation level as the concentration ...

Embodiment 3

[0107] A targeting chimera (represented by LB-Pi-A14-TH), whose structure is as follows image 3 As shown in A, its ERK1 / 2 degradation effect is verified by experiments:

[0108] (1) in 6-well plate with 5×10 5 The density of granule cells / well was planted into PC9 non-small cell lung cancer cell line respectively, and treated with different concentrations of LB-Pi-A14-TH (0, 0.1, 0.3, 1, 3, 10 μM) for 6 hours, or 1 μM Different time points (0, 1, 3, 6, 12, 24 hours).

[0109] (2) After the cells adhere to the wall, add LB-Pi-A14-TH to start the treatment.

[0110] (3) The total protein was collected from the lysate, and after quantification, the expression levels of total ERK and phosphorylated RSK were detected by Western Blot.

[0111] Result analysis: Test results such as image 3 As shown in B, by Western Blot analysis, LB-Pi-A14-TH treatment can effectively promote the degradation of ERK1 / 2 and the decrease of RSK phosphorylation level as the concentration increase...

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Abstract

The invention relates to the technical field of inhibitors, in particular to a targeting chimera for degrading ERK1 / 2 protein and application of the targeting chimera. The targeting chimera has the following chemical structure: in the formula, L is a rigid linking group or a hydrophilic linking group, M is a ubiquitin ligase ligand molecule, and n1 is an integer from 0 to 20; r1 and R3 are respectively and independently selected from any one of hydrogen, halogen, hydroxyl, amino, nitro, alkyl, alkoxy alkyl, aryl and ester group; r2 is selected from at least one of hydrogen, alkyl, halogen, alkoxy, nitrogen-containing heterocyclic ring, alkylene oxide and cyclopropane. The targeting chimera can effectively and specifically degrade ERK1 / 2 and inhibit tumor growth, so that the clinical problem of ERK1 / 2 mutation drug resistance can be solved, and therefore, the targeting chimera has a very good application prospect in preparation of antitumor drugs.

Description

technical field [0001] The application belongs to the technical field of inhibitors, and in particular relates to a targeting chimera for degrading ERK1 / 2 protein and its application. Background technique [0002] Protein degradation targeting chimeras (Proteolysis Targeting Chimeras, PROTAC) is a hybrid bifunctional small molecule compound, the structure contains two different ligands, one is the ubiquitin ligase E3 ligand, the other is the target in the cell The ligand bound by the target protein, the two ligands are connected by a linker (Linker), thus forming a "triple" compound: target protein ligand-Linker-E3 ligand. The ubiquitination tag is added to the target protein by E3 ligase, which initiates a powerful ubiquitination hydrolysis process in the cell, and specifically degrades the target protein through the ubiquitin-proteasome pathway. [0003] Extracellular regulated protein kinases (ERK1 / 2) are kinases closely related to tumors. According to research reports, ...

Claims

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Application Information

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IPC IPC(8): C07D405/14C07K5/062C07K1/107A61P35/00
CPCC07D405/14C07K5/06034A61P35/00
Inventor 郑多朱礼志江承尧黄均荣陈春兰
Owner SHENZHEN UNIV
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