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Application of compound as inhibitor of targeted phosphoglycerate kinase PGK1

A technology to phosphoglycerate kinase and compounds, applied in the application field of inhibitors, can solve problems such as activation defects

Pending Publication Date: 2022-04-26
SHENZHEN READLINE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, TZ has certain defects in the activation of PGK1

Method used

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  • Application of compound as inhibitor of targeted phosphoglycerate kinase PGK1
  • Application of compound as inhibitor of targeted phosphoglycerate kinase PGK1
  • Application of compound as inhibitor of targeted phosphoglycerate kinase PGK1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Effect of PQ (paraquat)-induced oxidative stress model in Drosophila

[0075] Drosophila w 1118 They were raised in a biochemical incubator with the temperature set at 25°C on a mixture containing 20g corn flour, 5.875g yeast, 1.625g agar, 34.375g sucrose, 0.5g sodium benzoate, 3.1mL propionic acid and 1L water. There were 20 fruit flies in each group.

[0076] Select a compound with the structure shown in formula I-1, which has the structure shown in formula I-1-1;

[0077]

[0078] Select a compound with the structure shown in formula I-2, which has the structure shown in formula I-2-1;

[0079]

[0080] A control group and an experimental group were set up for each compound. Control group: Drosophila was treated with a compound solution prepared in sucrose solution with a mass concentration of 0.002% for 48 hours; the purpose of the control group was to prove that the compound had no effect on the normal survival of fruit flies at this concentration. Experi...

Embodiment 2

[0083] Effect on PGK1 activation

[0084] To induce the expression of PGK1 in vitro, the cDNA of human PGK1 was cloned into the pET28a(+) vector containing His tag. Protein expression was induced with 0.5 mM IPTG. 5 mM IPTG induces protein expression in BL21(DE3) chemically competent cells. After lysing cells in extraction buffer (20 mM sodium phosphate, 500 mM sodium chloride, 5 mM imidazole, 5% glycerol, protease inhibitor cocktail (100-fold concentrated DMSO solution), pH 7.9), the supernatant was washed with nickel beads ( AdarBiotech) purification. Elution buffer (20 mM sodium phosphate, 500 mM sodium chloride, 80 mM imidazole, 5% glycerol, protease inhibitor cocktail (100-fold concentrated DMSO solution), pH 7.9) was used to elute His-tagged PGK1. To measure PGK1 activity, a saturating amount of substrate (1.6 mM GAP, 1 mM (βNAD, 1 mM ADP, 20 ng / μL GAPDH) was mixed with purified recombinant mouse PGK1 His protein (2 μg / mL) and added in buffer (20 mM Tris, 100mM NaCl,...

Embodiment 3

[0087] Protective effect on nerve cell ischemia and hypoxia injury

[0088] Rat pheochromocytoma cells (PC12 cells) were inoculated in 96-well plates, cultured until adherent, and then divided into control group, OGD / R1 group and OGD / R2 group. The control group was treated with Dulbecco's modified Eagle's medium (DMEM, HyClone) at a volume concentration of 95% O 2 , 5%CO 2 cultured in an incubator. Add compound formula Ⅰ-1-1 (12.5~1.5625μM) to OGD / R1 group, add compound formula Ⅰ-2-1 (12.5~1.5625μM) to OGD / R2 group, at a volume concentration of 95% O 2 , 5%CO 2 cultured in an incubator for 24 h. Then change to the sugar-free medium (Beijing Sunshine Biotechnology Co., Ltd.) 2 , 5%CO 2 and 1%O 2 ) for 12 hours. Replace with DMEM medium containing glucose, and at 37 °C with a volume concentration of 95% O 2 , 5%CO 2 Incubate for 24 h in an incubator for reoxygenation.

[0089] image 3 The effects of different concentrations of compounds on the viability of PC12 cell...

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Abstract

The invention relates to the technical field of research and development of medicines, in particular to application of a compound serving as an inhibitor of targeted phosphoglycerate kinase PGK1. The compound has a structure as shown in a formula I; wherein R1 is selected from a structure as shown in a formula II or a formula III; r < 2 >, R < 3 >, R < 4 > and R < 7 > are independently selected from hydrogen or C1-C30 alkyl groups; r5 is selected from the group consisting of substituted or unsubstituted C6-C30 aryl groups; and R6 is selected from hydrogen, C1-C30 alkyl or halogen. Biological experiment verification is carried out on the compound with the structure as shown in the formula I, and it is found that the compound has the anti-oxidative stress effect through a fruit fly model induced by PQ toxin; an enzyme activity experiment shows that the compound can activate PGK1 in a certain range; a cell hypoxia ischemia model finds that the compound has a neuroprotective effect; through flow and western blot experiments, it is found that the compound has the effects of resisting inflammation and inhibiting cell apoptosis.

Description

technical field [0001] The invention relates to the technical field of drug research and development, in particular to the application of a compound as an inhibitor targeting phosphoglycerate kinase PGK1. Background technique [0002] Cerebral Stroke, also known as stroke, is a group of diseases caused by brain tissue ischemia and hypoxia caused by cerebral blood vessel blockage or rupture, which in turn causes brain tissue damage. It has high morbidity, high disability rate, high mortality rate and High recurrence rate (Stroke and stroke care in China: huge burden, significant workload, and national priority. Stroke 2011, 42, 3651-3654.). The most common cause of ischemic stroke is that there is a thrombus on the inner wall of the blood supply vessel of the brain, which leads to arterial embolism after falling off, causing acute nerve cell death and delayed nerve cell death. The latter is mainly a kind of programmed cell death, namely Apoptosis (Delayed neuronal death in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12A61K31/4196A61P25/00A61P29/00
CPCC07D249/12A61K31/4196A61P25/00A61P29/00
Inventor 强少佳付成功吴俞印于铁妹潘俊锋刘建
Owner SHENZHEN READLINE BIOTECH CO LTD
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