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Drug target for treating cancer and application thereof

A technology of drugs and targets, applied in the field of biomedicine, to achieve good medicinal prospects and strong pharmacological effects

Pending Publication Date: 2022-06-21
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, no inhibitors of PITPs have been found, so it is very important to use PITP as a target, develop corresponding highly selective inhibitors, regulate specific phosphoinositide signaling pathways in cells, and then achieve the treatment of related diseases

Method used

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  • Drug target for treating cancer and application thereof
  • Drug target for treating cancer and application thereof
  • Drug target for treating cancer and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Synthesis of Microcolin H and derivatives

[0060] The invention decomposes the natural product Microcolin H into three fragments, M1, M2 and M3, respectively completes the synthesis of the three fragments M1, M2 and M3, then condenses the three fragments step by step, and finally obtains the natural product Microcolin H.

[0061]

[0062]

[0063] 1.1 Preparation of Microcolin H

[0064] 1) Preparation of M1:

[0065]

[0066] (R)-2-Methyloctanoic acid (M1)

[0067] Dissolve 3.5 g (11.6 mmol) of (R)-4-benzyl-3-octanoyloxazolidin-2-one (3) in 15 mL of THF, add 12.7 mL (12.7 mmol) of NaHMDS dropwise at -78°C, Stir for 30 min, then add 1.45 mL (23.2 mmol) MeI, and react at -78°C for 5 h. After the reaction was completed, it was quenched with saturated ammonium chloride, extracted three times with EtOAc (100 mL), and the organic phases were combined and 5% Na was used. 2 S 2 O 3 , extracted once with saturated brine, and purified by column chromato...

Embodiment 2

[0161] Example 2 Testing the activity of Microcolin H and derivative molecules on tumor cells

[0162] Various cancer cells were prepared into 50,000 cells / ml cell suspension, added to a 96-well plate cell culture dish, and the compounds synthesized in Example 1 were added respectively. Each test concentration was 6 wells, and set at 37°C, 5% CO. 2 After culturing for 48 hours under saturated humidity conditions, the absorbance A value was measured by the CCK8 method at a wavelength of 450 nm in an enzyme-linked detector, and the inhibitory effect of the compounds of the present invention on the test cancer cells was calculated.

[0163] Table 1 Inhibitory activity of Microcolin H on various tumor cells

[0164] cell HuH-7 HepaRG HGC-27 AGS MKN-28 A549 H460 AsPC-1 PANC-1 Hela IC 50 (nM)

1.3 5.7 3.5 8.6 50.2 0.7 10.1 3.5 2.5 132.6

[0165] The activity test shows that the marine polypeptide Microcolin H is effective on human l...

Embodiment 3

[0170] Example 3 Investigating the direct action target of Microcolin H in tumor cells

[0171] The present invention utilizes the probe molecule Probe 5 synthesized in Example 1 to incubate with cell lysate or living cells, and after incubation, the alkynyl part of the probe and the reagent rhodamine-azide undergo a "click chemistry" reaction, and the target that Microcolin H binds to The protein will have a rhodamine fluorescent label. After SDS-PAGE separation, the target protein of Microcolin H can be found by fluorescence imaging. The specific experimental process is as follows:

[0172] Different concentrations of probe molecules (probe 5 concentration: 0.01 μM, 0.1 μM, 1.0 μM) were incubated with gastric cancer cell HGC lysate, while the control group (25 μM concentration) was competed with 25 μM parent molecule Microcolin H as a cold probe, 1 After hours, the fluorescent reagents Rhodamine-azide (10 μM), 100 μM TBTA, 1 mM TCEP, and 1 mM CuSO were added 4 The Click rea...

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Abstract

The invention relates to a drug target for treating cancer and application thereof. The invention relates to application of polypeptide Microcolin H and analogues thereof in preparation of medicines. The medicines comprise medicines for treating neurodegenerative diseases, medicines for treating neurodegenerative diseases, medicines for treating neurodegenerative diseases, medicines for treating neurodegenerative diseases and medicines for treating neurodegenerative diseases. The invention discloses a medicine for treating Duchenne muscular dystrophy. A drug for the treatment of inflammatory diseases; a medicament for treating cardiovascular diseases; the invention discloses a medicine for treating cancers. The invention provides an application of an inhibitor of phosphatidyl alcohol transporter as an anti-tumor drug, and the inhibitor is used as a drug target to develop a therapeutic drug for cancer, cardiovascular diseases and other diseases; the natural polypeptide Microcolin H as well as the analogue and the derivative thereof can accurately target the phosphatidyl alcohol transporter, so that efficient inhibition on tumor cells is realized, the pharmacological action is strong, and the natural polypeptide Microcolin H can be used as the first high-activity and high-selectivity inhibitor of the novel drug target phosphatidyl alcohol transporter, and has a good medicinal prospect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and particularly relates to a drug target for treating cancer and its application. Background technique [0002] Lipid signaling regulates a wide range of cellular processes, including regulation of G protein-coupled receptors and receptor tyrosine kinases at the plasma membrane, actin dynamics, transcription, and membrane trafficking. Eukaryotic lipid signaling relies primarily on phosphoinositides (PtdIns) and soluble inositol phosphates derived from them. [0003] Phosphatidylinositol is an essential phospholipid that acts as a metabolic precursor for phosphoinositide and Ins-phosphate. Although the inositol-phosphate forms are chemically diverse, the phosphoinositide molecular chain is relatively simple. Mammals produce seven phosphoinositides: including phosphatidyl alcohol-3-phosphate, phosphatidyl alcohol-4-phosphate, phosphatidyl alcohol-5-phosphate, phosphatidyl alcohol-4,5-bisphos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/07A61K45/00A61P35/00A61P9/00A61P29/00A61P25/00A61P21/00G01N33/53G01N33/574G01N33/68
CPCA61K38/07A61K45/00A61P35/00A61P9/00A61P29/00A61P25/00A61P21/00G01N33/94G01N33/57484G01N33/6893G01N33/6896G01N2333/47G01N2800/28G01N2800/2857G01N2800/2821G01N2800/2835G01N2800/32G01N2800/2878
Inventor 王锐张海龙杨瀚舸王聪侯彦喆黄珊
Owner LANZHOU UNIVERSITY
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