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An antagonistic short peptide targeting FGFR1

A technology of FGFR1 and short peptides, which is applied in the direction of peptides, antineoplastic drugs, peptide/protein components, etc., can solve the problems of easy degradation, short half-life, and lagging research on FGFR1 antagonistic peptides, and achieve long half-life, stable secondary structure, good Effect of antitumor activity

Active Publication Date: 2021-08-03
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The delay in research on FGFR1 antagonistic peptides is mainly related to its easy degradation and short half-life

Method used

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  • An antagonistic short peptide targeting FGFR1
  • An antagonistic short peptide targeting FGFR1
  • An antagonistic short peptide targeting FGFR1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Ser-Pro-Pro-Arg-Tyr-Pro-Gly-Gly-Gly-Ser-NH 2

[0046]The experimental results show that, compared with the precursor peptide P9, the degraded short peptide compound P48 found in the present invention has a stable secondary structure and a relatively prolonged half-life. In addition, molecular docking experiments found that the short peptide compound P48 can form stable hydrogen bonds with FGFR1. It was found by SPR experiment that P48 can competitively bind to FGFR1 with bFGF, and the higher the concentration, the stronger the binding force (Example 1).

[0047] At the same time, Western blot experiments found that in highly transformed human embryonic kidney cells HEK-293 and fibroblast MEF-WT, Balb / c 3T3, the short peptide compound P48 can concentration-dependently inhibit the activation of FGFR1 induced by bFGF ( Example 2). In addition, the inhibitory effect of the short peptide compound P48 on FGFR1 signaling is similar to that of SSR, and it has no obvious inhi...

Embodiment 2

[0059] Inhibitory activity of short peptide compound P48 on FGFR1 signaling pathway in highly transformed human embryonic kidney cells and fibroblasts:

[0060] Human embryonic kidney cells HEK-293 and fibroblasts MEF-WT and Balb / c 3T3 were seeded in 6-well plates respectively. After the cells adhered overnight, they were pretreated with P48 for 10 minutes or AZD4547 / PD173074 / SSR for 2 hours, and incubated with bFGF for 15 minutes. figure 2 A represents the inhibitory effect of P48 / AZD4547 / PD173074 on FGFR1 and its downstream proteins (FRS2α, ERK1 / 2, AKT) in HEK-293, MEF-WT, and Balb / c3T3 cells. figure 2 B represents the inhibition of P48 / AZD4547 / SSR on the downstream protein PLCγ of FGFR1 in MEF-WT cells. figure 2 C indicates the binding ability of P48 to FGFR1 in MEF-WT and FGFR1-FGFR2-FRS2α knockout MEF cells. The experimental steps are as follows: MEF-WT and MEF KO(FGFR1-FGFR2-FRS2α) cells (1×10 6 cells / ml) in a 35 mm culture dish. After the cells adhered to the wa...

Embodiment 3

[0062] The inhibitory activity of the short peptide compound P48 on the FGFR1 signaling pathway of various tumor cells:

[0063] Cervical cancer cells Hela229, melanoma B16-F10, lung cancer cells NCI-H460, and gastric cancer cells SGC-7901 and MGC-803 were seeded in 6-well plates, respectively. After the cells adhered overnight, they were pretreated with P48 for 10 minutes or AZD4547 / SSR for 2 hours, and incubated with bFGF / aFGF for 15 minutes or KGF for 20 minutes. image 3 A represents the inhibition of P48 / AZD4547 on FGFR1 and its downstream proteins (FRS2α, ERK1 / 2, AKT) in Hela229, B16-F10, NCI-H460, MGC-803, SGC-7901 cells under bFGF stimulation. image 3B represents the inhibition of FGFR1 and its downstream proteins (FRS2α, ERK1 / 2) in SGC-7901 cells by P48 / AZD4547 / SSR under bFGF stimulation. image 3 C represents the inhibition of P48 on FGFR1 and its downstream proteins (FRS2α, ERK1 / 2) in SGC-7901 cells under the stimulation of bFGF / aFGF / KGF. image 3 D represents th...

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Abstract

The invention belongs to the field of short peptide pharmacology, specifically relates to the stability research of FGFR1 antagonistic short peptides and its application in the field of anti-tumor, and discloses a FGFR1 antagonistic short peptide, including short peptide compound P48, which inhibits the FGFR1 pathway , inhibit cell proliferation and migration. With the above-mentioned technical solution, the present inventor obtained the short peptide compound P48 through unremitting efforts, and found that it has a stable secondary structure and a relatively long half-life. In addition, the short peptide compound P48 can effectively target and inhibit FGFR1, exhibit good anti-tumor activity in vivo and in vitro, and is expected to become a candidate peptide inhibitor drug for cancer treatment.

Description

technical field [0001] The invention relates to the technical field of short peptide pharmacology, in particular to an antagonistic short peptide targeting FGFR1. Background technique [0002] Fibroblast growth factor receptor 1 (FGFR1) is involved in the occurrence and development of various tumors including breast cancer, lung cancer, bladder cancer, ovarian cancer, pancreatic cancer, and gastric cancer. FGFR1 is an effective target for cancer therapy. At present, there is no FGFR1 inhibitor approved for marketing, and it is of great research value to find effective FGFR1-targeted inhibitors. [0003] Targeted inhibitors are mainly divided into small molecule inhibitors, antibody drugs, peptide inhibitors and their derivatives. Compared with small molecule inhibitors, peptide inhibitors have high affinity and specificity, and have lower adverse reactions. Compared with antibody drugs, peptide inhibitors have lower molecular weight and stronger penetration activity on ti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06A61K38/08A61P35/00
CPCA61K38/00A61P35/00C07K7/06
Inventor 吴建章李物兰陈玲姿范蕾蔡跃飘
Owner WENZHOU MEDICAL UNIV
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