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Application of small molecule compound in preparation of urokinase receptor inhibitor medicine

A small molecule compound, urokinase receptor technology, applied in the field of medicine

Pending Publication Date: 2022-08-09
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, there has never been any report on diltiazem or glibenclamide having urokinase receptor uPAR inhibitory activity

Method used

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  • Application of small molecule compound in preparation of urokinase receptor inhibitor medicine
  • Application of small molecule compound in preparation of urokinase receptor inhibitor medicine
  • Application of small molecule compound in preparation of urokinase receptor inhibitor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Determination of the binding strength of diltiazem and glyburide to uPAR by surface plasmon resonance (SPR).

[0026] experimental method:

[0027] To determine the equilibrium dissociation constants (K D ), surface plasmon resonance analysis was performed on a BIACORE T200 instrument (BIACORE, Uppsala, Sweden). Coupling of uPAR(H47C / N259C) to the CM5 chip was performed by injecting uPAR(H47C / N259C) protein at a concentration of 30 μg / mL in coupling buffer (10 mM sodium acetate, pH 5.0) to achieve a coupling level of approx. 500 reaction units (RU). Surface blocking with ethanolamine after coupling. A reference channel was prepared in the same way without coupling uPAR (H47C / N259C). Running buffer (20 mM pH7.5 HEPES + 0.15 M NaCl + 0.005% (w / v) containing 100 μM small molecule compound diltiazem or glyburide) was injected at 25 °C at a flow rate of 30 μL per minute. Tween20). Subsequently, dissociation was monitored for 300 seconds. Record the increase...

Embodiment 2

[0030] Example 2: Transwell invasion assay to identify the in vitro anti-tumor metastatic efficacy of diltiazem and glyburide.

[0031] experimental method:

[0032] For migration experiments, place 5 x 10 in serum-free medium 4 Individual cells (HEK-293T-uPAR cells, or PC-3 cells or Caco-2 cells) were placed in the upper chamber of a Transwell permeable scaffold with a cell culture insert with 8 μm pores. PC-3 cells and Caco-2 cells were purchased from Shanghai Institute of Cell Research, Chinese Academy of Sciences. HEK-293T-uPAR cells highly expressed urokinase receptor (uPAR), which was provided by the School of Chemistry, Fuzhou University. For invasion experiments, the preparation of BD Matrigel-coated chambers was done in strict accordance with the operating instructions provided by the Corning supplier. Briefly, 100 μL of a 50-fold dilution of BD Matrigel at a concentration of approximately 0.2–0.3 mg / mL was spread on the upper chamber of a Corning Transwell chamber a...

Embodiment 3

[0035] Example 3: The mouse CT-26 tumor model verifies the anti-tumor effects of diltiazem and glyburide in vivo.

[0036] experimental method:

[0037] will be about 10 7 Viable CT-26 cells (CT-26 cells were purchased from Shanghai Institute of Cell Research, Chinese Academy of Sciences) were suspended in 200 μL of sterile saline and inoculated into the lower right side of the back of each Balb / c mouse. When a palpable tumor was detected, the size of the tumor was monitored daily with a vernier caliper. The volume of the tumor was calculated using the modified ellipsoid formula 1 / 2 × (length × width 2 )computational. When tumor volume reaches 80-100 mm within 3-5 days after inoculation 3 , mice were randomly divided into three groups (5 mice in each group), and the average starting tumor size (80-120 mm) 3 ) and body weight (20~25 grams). Mice were orally administered normal saline, 100 mg / kg diltiazem, or 300 mg / kg glyburide every two days for 14 days. The body weight...

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Abstract

The invention discloses an application of a small molecule compound in preparation of a urokinase receptor inhibitor drug. The small molecular compound is diltiazem or glibenclamide. The invention discovers that diltiazem and glibenclamide have urokinase receptor (uPAR) inhibitory activity for the first time, can be applied to preparation of medicines for treating diseases related to urokinase and / or pathological overexpression of urokinase receptors, and has a wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to the application of a small molecule compound in the preparation of a urokinase receptor inhibitor medicine. Background technique [0002] Urokinase receptor, also known as urokinase-type plasminogen activator receptor (uPAR), is a membrane-anchored glycoprotein that has been shown to be closely related to multiple processes in various diseases such as tumor development and metastasis related. Specifically, uPAR, together with its ligand urokinase-type plasminogen activator (uPA), was found to be overexpressed on the surface of most tumor cells, including prostate, breast and other malignant tumor cells. uPAR includes a membranous glycosylphosphoinositide anchor and three Ly6 / uPAR / α-neurotoxin-like domains that form a pocket to accommodate uPA. uPA has been shown to be responsible for activating the extracellular fibrinolytic system in the tumor microenvironment. Activates a v...

Claims

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Application Information

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IPC IPC(8): A61K31/554A61K31/64A61P35/00A61P35/04
CPCA61K31/554A61K31/64A61P35/00A61P35/04
Inventor 李金宇徐芃周阳宋美如谢道情鄢树枫黄明东
Owner FUZHOU UNIV
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