Application of Erbin inhibitor in preparation of antitumor drug

A technology of anti-tumor drugs and inhibitors, which is applied in the application field of Erbin inhibitors in the preparation of anti-tumor drugs, and can solve the problems of easy recurrence and drug resistance of patients

Inactive Publication Date: 2013-07-24
梅林 +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these drugs often lead to drug resist...

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  • Application of Erbin inhibitor in preparation of antitumor drug
  • Application of Erbin inhibitor in preparation of antitumor drug
  • Application of Erbin inhibitor in preparation of antitumor drug

Examples

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Embodiment 1

[0035] Example 1: Cell models and animal models are used to confirm that Erbin is extremely important to the generation and development of ErbB2-dependent breast cancer, providing a way and means to treat ErbB2-dependent tumors by knocking down the expression of Erbin with specific shRNA

[0036] To study the effect of Erbin on breast cancer cell proliferation, ErbB2-dependent breast cancer cell lines BT474 (ATCC) and SKBR3 (ATCC), and ErbB2-independent breast cancer cell line ZR751 (Public Health England) were selected. When these cells were cultured to full plate, shRNA specifically recognizing Erbin (shErbin) packaged in lentivirus (forward strand: 5'TGCAT CCCTC TAGAG AACAA CTTTC AAGAG AAGTT GTTCTCTAGA GGGAT GCTTT TTTC; reverse strand: 5'TCGAG AAAAA AGCAT CCCTCTAGAG AACAA CTTCT CTTGA AAGTT GTTCT CTAGA GGGAT GCA.) and another control shRNA (shCtrl) (pLL3.7 empty vector) respectively invaded the cells (the titer was 8x10 8 Add 1 μl of IU / ml virus particle suspension into a 10...

Embodiment 2

[0040] Example 2: Cell models and animal models were used to confirm that the PDZ structural fragment of Erbin is extremely critical for ErbB2-dependent breast cancer formation. Overexpression of the PDZ fragment of Erbin can interfere with the interaction of Erbin-ErbB2 to reduce the protein level of ErbB2 and its kinase activation, thus providing a therapeutic approach and means for treating ErbB2-dependent tumors by targeting the PDZ fragment of Erbin

[0041] Earlier work by the inventors has revealed that Erbin binds to ErbB2 through the PDZ structural region. The PDZ structural fragment at the C-terminus of Erbin and the PDZ-binding sequence at the C-terminus of ErbB2 are critical for their binding and interaction. To investigate whether the binding of Erbin to ErbB2 is important for Erbin to regulate the protein stability and function of ErbB2, a plasmid expressing only the PDZ structural fragment of Erbin was constructed

[0042] (ATGGAGATTCGAGTGAGGGTTGAAAAGGATCCAGAAC...

Embodiment 3

[0081]Example 3: Cell models and animal models confirm that the C-terminal polypeptide fragment of ErbB2 can interfere with Erbin-ErbB2 interaction to reduce the protein level and kinase activity of ErbB2 in cancer cells, providing an exogenous C-terminal of excessive ErbB2 Ways and means of treating tumors with polypeptide B2tail

[0082] In order to develop an easy-to-apply therapeutic approach targeting Erbin-ErbB2 interaction, a polypeptide fragment B2tail (PTAENPEYLGLDVPV) containing 15 amino acid residues at the end of ErbB2 was synthesized. Myc-Erbin and Flag-ErbB2 plasmids were transfected into HEK293 cells, and the cells were lysed one day after protein expression. Equal amounts of cell lysate containing Myc-Erbin and Flag-ErbB2 proteins were mixed with 200 μl of 50 μM B2tail polypeptide or unrelated polypeptide (Ctrl) and incubated for one hour, and then immunoprecipitated with anti-Myc antibody. The immunoprecipitated products were detected by Western blotting, and...

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Abstract

The invention provides application of an Erbin inhibitor in preparation of an antitumor drug. The inhibitor is specifically a compound capable of lowering expression of Erbin or interfering Erbin-ErbB2 interaction. The Erbin-Erbin interaction is crucial to tumor-prompting action and carcinogenic action of ErbB2; the ErbB2 dependent cancer cell proliferation or tumor growth can be inhibited by over-expressing a PDZ structural segment of Erbin or excessively giving tail-end polypeptide segments to the ErB2 in the cell. The invention provides a novel way of treating ErbB2 positive tumors, i.e., a way of inhibiting protein stability and kinase activity of the ErbB2 by reducing the expression of Erbin or interfering with the combination of ErBin and ErbB2, so that the tumor-prompting action and carcinogenic action of the ErbB2 are inhibited.

Description

(1) Technical field [0001] The invention relates to the application of Erbin inhibitors in the preparation of antitumor drugs. (2) Background technology [0002] Receptors of the endothelial growth factor (Epidermal growth factor receptor) family, including EGFR (also known as HER1, ErbB1), ErbB2 (HER2, neu), ErbB3 (HER3) and ErbB4 (HER4) are involved in the formation and development of tumors. Among them, ErbB2 has attracted special attention, because the overexpression of ErbB2 has been detected in more than 25% of breast cancer tissues, and breast cancer patients with ErbB2 overexpression often have high recurrence, easy metastasis and poor prognosis. In addition to breast cancer, ErbB2 overexpression has also been implicated in ovarian, gastric and uterine cancers. ErbB2 was originally discovered as a transformation-causing proto-oncogene (an oncogene carcinomaogen-induced neuroblastoma, neu; or an oncogene of avian erythoblastosis virus, ErbB2). As a member of the end...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K38/16A61K38/10A61K48/00A61K31/7088C07K7/08C07K14/00C12N15/11A61P35/00
Inventor 梅林陶艳梅沈承勇熊文诚罗时文
Owner 梅林
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