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Anti-tumor covalent polypeptide inhibitor targeting grb2 protein and its preparation method and application

A polypeptide inhibitor and anti-tumor technology, which is applied in the fields of molecular biology and medicine, and can solve problems such as poor therapeutic effect, large drug side effects, and off-target

Active Publication Date: 2020-03-24
SHANGHAI FIRST MATERNITY & INFANT HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Covalent inhibitor drugs targeting the Grb2 protein also have the problem of "off-target" in the treatment of breast cancer, resulting in large drug side effects and poor therapeutic effect

Method used

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  • Anti-tumor covalent polypeptide inhibitor targeting grb2 protein and its preparation method and application
  • Anti-tumor covalent polypeptide inhibitor targeting grb2 protein and its preparation method and application
  • Anti-tumor covalent polypeptide inhibitor targeting grb2 protein and its preparation method and application

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Effect test

Embodiment 1

[0027] 1. Synthesis and characterization of covalent peptide inhibitor RP

[0028] 1 method

[0029] 1.1 Synthesis of covalent peptide inhibitor RP

[0030] 1) Use Fmoc chemical solid-phase peptide synthesis, use Rink Amide-ChemMatrix resin, use 5-fold excess Fmoc-protected amino acids and condensation reagents (HBTU / HOBt) to synthesize peptides, where the precursor of X is Fmoc-Dap(Mtt)- Oh.

[0031] 2) The first amino acid Fmoc at the N-terminus of the polypeptide is deprotected and protected with acetic anhydride.

[0032] 3) Selectively deprotect the Mtt of the X precursor with 1% TFA, add chloroacetic acid, and modify the side chain into an acid chloride.

[0033] 4) Use 95% TFA to remove the polypeptide from the resin, precipitate it with glacial ether, and use HPLC to separate and purify the obtained preliminary polypeptide.

[0034] 1.2 Characterization of covalent peptide inhibitor RP

[0035] The peptides separated and purified by HPLC were detected and confirme...

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Abstract

The invention relates to a Grb2 protein targeting anti-tumor covalent polypeptide preparation and a preparation method and application thereof; the amino acid sequence of the covalent polypeptide preparation is VPPPVPPRRX, wherein X is (2S)-2-amino-3-[(2-chloracetyl)amino]propionic acid. The preparation method is Fmoc solid polypeptide synthetic method, and X is made from Fmoc-Dap(Mtt)-OH and chloroacetic acid. The covalent polypeptide inhibitor of the invention has high affinity to Grb2 protein and thereby is capable of avoiding 'off-target covalent reaction; therefore, the covalent polypeptide inhibitor has good treatment effect, and the problem that the prior art covalent polypeptide drugs have toxic and side effects is solved. A new idea to research and develop covalent inhibitor drugs is provided, and the treatment of diseases, such as breast cancer, is facilitated.

Description

technical field [0001] The invention relates to the technical fields of molecular biology and medicine, in particular to an anti-tumor covalent polypeptide inhibitor targeting Grb2 protein and its preparation method and application. Background technique [0002] Covalent inhibitors are the only class of drugs that can completely silence or permanently shut down disease-causing proteins among existing drug inhibitors. Valence reaction, thereby inhibiting the relevant activity of the target protein, so as to achieve the purpose of treating diseases. Compared with conventional non-covalent drugs, covalent drugs require less dosage and have long-lasting effects. In recent years, the US FDA and my country's CFDA have approved some of these drugs and applied them clinically. Due to the unique therapeutic advantages of covalent inhibitors, it has also been used in tumor therapy research, and some remarkable effects have been obtained. For example, Neubig and his colleagues used ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K38/08A61P35/00
CPCA61K38/00C07K7/06
Inventor 于永生冯茜
Owner SHANGHAI FIRST MATERNITY & INFANT HOSPITAL
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