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Anti-tumor small molecule peptide targeting FGFRs and application of anti-tumor small molecule peptide

A small-molecule peptide and anti-tumor technology, applied in the fields of biotechnology and medicine, can solve problems such as immunogenicity, multiple targets, and high toxicity

Active Publication Date: 2020-05-12
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there are small molecule inhibitors that block FGFRs signaling to achieve the effect of treating related tumors, such as Regorafenib, Lenvatinib, etc., but the small molecule drugs currently on the market mainly target the intracellular segment, which has the disadvantages of high toxicity and too many targets. Protein drugs can inhibit the receptor signal by blocking the combination of FGF and FGFR, and achieve the effect of treating tumor diseases by blocking the FGFRs signaling pathway, which has good biocompatibility, such as Cetuximab (cetuximab), Antibodies such as panitumumab
However, due to the large molecular weight of protein drugs, they are generally immunogenic when injected into the human body.

Method used

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  • Anti-tumor small molecule peptide targeting FGFRs and application of anti-tumor small molecule peptide
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  • Anti-tumor small molecule peptide targeting FGFRs and application of anti-tumor small molecule peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Screening of Small Molecular Peptides and Detection of Antitumor Effects

[0029] (1) Screening of small molecule peptides

[0030] The present invention is based on the phage display technology, relying on the non-covalent combination of a certain sequence of polypeptides and FGFR2, and incubating the recombinant protein of the extracellular segment of FGFR2 on a polystyrene plate (purchased from Yiqiao Shenzhou Science and Technology Co., Ltd., Beijing, article number 16483- H08H) PBS buffer solution, the protein is combined with the plate, and then the plate is processed through 5% (w / v) BSA (bovine serum albumin) blocking and washing with TBST buffer solution to contain 2.7*10 9 A phage expressing different short peptide sequences (purchased from New England Biolab, Beijing, trade name Ph.D.-12phage display peptide library kit) was co-incubated with the plate, unbound phage was eluted, and the phage that could bind was released in the large intestine of ER...

Embodiment 2

[0033] Example 2 Cellular level functional test of T1 polypeptide

[0034] ① Select the test cell line

[0035] Since FGFR2 has a certain expression level in SGC-7901 cells, various literatures have studied the biological functions of FGFR in SGC-7901 cells, especially the targeted inhibitors of the FGFR family. Whether the synthesized polypeptide has inhibitory effect on the proliferation of tumor cells was screened by Cell Counting Kit-8 from Shanghai Cell Bank.

[0036] ②Test method

[0037] A, SGC-7901 cells were cultured in DMEM medium supplemented with 10% (v / v) fetal bovine serum to the logarithmic phase, digested and collected cells, spread evenly in 96-well plate, cell density was 2000 / well, adherent After 24 hours, starve for 12 hours with serum-free DMEM medium, then replace the medium with DMEM medium supplemented with 5% (v / v) fetal bovine serum and add T1 polypeptide for 48 hours, and set 6 replicate wells for each concentration gradient ; Wherein, the final c...

Embodiment 3

[0041] Example 3: Detection of broad-spectrum anti-tumor properties of polypeptide T1

[0042] (1) Select the test cell line

[0043] Alternative cell lines are DU145 (human prostate cancer cells), Mda-Mb-231 (human gastric adenocarcinoma cells), EC9706 (human esophageal squamous cell carcinoma cells), A375 (human melanoma cells), the above four cell lines were purchased from Shanghai cell bank.

[0044] (2) Test method

[0045] The test method is the same as in Example 2, and the cell lines are DU145, Mda-Mb-231, EC9706, and A375.

[0046] (3) Test results

[0047] The result is as figure 2 As shown: T1 polypeptide has a certain level of inhibition on the proliferation of the above four cell lines, and all of them are concentration-gradient dependent. The maximum inhibitory efficiency can be obtained with a basic administration concentration of no more than 20 μM. This test shows that T1 polypeptide has a more obvious inhibitory rate on the four cell lines DU145, MM231, a...

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Abstract

The present invention discloses an anti-tumor small molecule polypeptide targeting FGFRs and an application of the anti-tumor small molecule peptide. An amino acid sequence of the anti-tumor small molecule peptide targeting the FGFRs is as follows: FPDSLYSSLFQL. The anti-tumor small molecule polypeptide can specifically bind to FGFR2, blocks an FGFRs signaling pathway, and achieves an anti-tumor effect. Therefore, the anti-tumor small molecule polypeptide can be used to prepare anti-tumor drugs or tumor diagnostic reagents for diagnosis or treatment of esophageal squamous carcinoma, stomach cancer, breast cancer, prostate cancer, melanoma, etc.

Description

technical field [0001] The invention belongs to the fields of biotechnology and medicine, in particular to an anti-tumor small molecule polypeptide targeting FGFRs and its application. Background technique [0002] Dysregulation of FGFRs (fibroblast growth factor receptor family) signaling is involved in the development, progression and treatment resistance of many tumor types. Gastric and breast cancer cell lines with high levels of FGFR2 amplification are highly sensitive to FGFR inhibitors in vitro. FGFR2 mutations have also been found in endometrial cancer, non-small cell lung cancer, and gastric cancer, mainly in the D2 and D3 regions of the extracellular domain of FGFR2, and mutations increase the efficiency of receptor dimerization, thereby enhancing the activation of FGFR signaling. FGFRs can be used as the target of targeted tumor therapy. Its family includes four subtypes of FGFR1, FGFR2, FGFR3, and FGF4. Since a variety of tumors have abnormal FGFR signaling, sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61K38/10A61P35/00G01N33/68G01N33/574
CPCA61K38/00A61P35/00C07K7/08G01N33/574G01N33/6872
Inventor 陈小佳洪岸王强
Owner JINAN UNIVERSITY
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