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Application of phosphatidyl inositol 4-position kinase type II alpha subtype specific inhibitor PI-273

A PI-273, 1. PI-273 technology, applied in the field of application of PI-273, a specific inhibitor of inositol phospholipid kinase type 2 α subtype, can solve the problem that it is difficult to distinguish inhibitory kinases

Active Publication Date: 2016-02-17
INSITUTE OF BIOPHYSICS CHINESE ACADEMY OF SCIENCES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the nucleic acid binding pockets of different isoforms of the PIK family have highly conserved amino acid sequences, it is difficult for small molecule inhibitors to differentiate and inhibit different isoforms of kinases

Method used

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  • Application of phosphatidyl inositol 4-position kinase type II alpha subtype specific inhibitor PI-273
  • Application of phosphatidyl inositol 4-position kinase type II alpha subtype specific inhibitor PI-273
  • Application of phosphatidyl inositol 4-position kinase type II alpha subtype specific inhibitor PI-273

Examples

Experimental program
Comparison scheme
Effect test

Embodiment PI4

[0085] Following embodiment PI4P content detection method is as follows:

[0086] Resuspend the sample with 5 μl of CHCl3:MeOH:H2O (1:2:0.8) mixture, apply it to the PI4P membrane after ultrasonication in an ice-water bath for 5 minutes; block with 3% BSA in PBS-T solution for 1 hour and add 5 mL of PI4P detection solution (sales company: Echelon Biosciences, catalog number: K-4000), incubated at room temperature for 1 hour; with PBS-T solution (10 mM phosphate, 2.7 mM potassium chloride, 137 mM sodium chloride, 0.1% Tween-20, pH7.4) wash 3 times for 5 minutes each time; add 5mL PI4P secondary antibody detection solution (sell company: Echelon Biosciences, catalog number: K-4000), incubate at room temperature for 1 hour; wash 3 times with PBS-T solution for 5 minutes each time ; detection of chemiluminescence signal.

[0087] The above CHCl3:MeOH:H2O (1:2:0.8) mixed solution is a mixed solution obtained by mixing CHCl3, MeOH and H2O according to a volume ratio of 1:2:0.8.

...

Embodiment 1

[0090] Example 1, Screening of PI-273, a small molecule inhibitor of PI4KIIα

[0091] The amino acid sequence of PI4KIIα is sequence 1.

[0092] Based on the structure of PI4KIIα, potential small molecule inhibitors were screened virtually from the SPECS compound library, and 142 compounds were finally selected. The inhibitory effect of these compounds on PI4KIIα was detected at 100 μM, and the half inhibitory concentration of the compounds on PI4KIIα was further determined. Among them, PI-93 showed the best inhibitory effect. According to the chemical structure of PI-93, 53 candidate compounds were selected, among which PI-273 had IC in vitro enzyme activity assay 50 0.47μM, significantly inhibited the growth of three breast cancer MCF-7, Hs578T, T-47D cell lines. After PI-273 treatment of MCF-7 cells, the content of PI4P decreased. PI-273 is a potent inhibitor of kinase activity of PI4KIIα.

[0093] For the screening of PI-273 (the structural formula is formula 1), see ...

Embodiment 2

[0096] Example 2, PI-273 inhibits PI4KIIα enzyme activity

[0097] 1. PI-273 directly binds to PI4KIIα and reversibly inhibits PI4KIIα

[0098] Detect whether PI-273 and its analogues PI-69, PI-277, and PI-282 interact with PI4KIIα. The following compounds are PI-273, PI-69, PI-277, and PI-282, respectively. details as follows:

[0099] The structural formula of PI-69 is shown in Formula 2:

[0100]

[0101] The structural formula of PI-277 is shown in formula 3:

[0102]

[0103] The structural formula of PI-282 is shown in formula 4:

[0104]

[0105] 1) Surface plasmon resonance experiment

[0106] Surface plasmon resonance experiments were carried out on BiacoreT200 of GE Company. PI4KIIα protein was covalently immobilized on a CM5 chip, and the chip was equilibrated in HBS-EP solution containing 10mM HEPES (pH7.4), 150mM NaCl, 3mM EDTA, 0.05% (v / v) surfactant P20, 0.1% (v / v) DMSO ;

[0107] PI-273, PI-69, PI-277 and PI-282 were diluted in equal gradients and...

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Abstract

The invention discloses application of phosphatidyl inositol 4-position kinase type II alpha (PI4KIIalpha) subtype specific inhibitor PI-273 and provides application of the PI-273 in PI4KIIalpha enzyme inhibitor as well as application of the PI-273 in preparation of a product for inhibiting the enzyme activity of the PI4KIIalpha. Experiments in the invention show that subtype specific small-molecule inhibitor of the PI4KIIalpha is screened according to a crystal structure of a human PI4KIIalpha for the first time; the PI-273 can be used for significantly inhibiting the growth of tumor tissues induced by MCF-7; the PI4KIIalpha subtype specific inhibitor PI-273 provides a new strategy for treating breast cancer.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to the application of PI-273, a specific inhibitor of inositol phospholipid kinase 4-position α subtype (PI4KIIα). Background technique [0002] The inositol phospholipid (PI) signaling pathway plays a central role in transmembrane signal transduction and signaling pathways for the regulation of cell growth by various growth factors and hormones. Inositol phospholipid 4-position kinase PI4K is the first kinase that plays an important role in the PI signaling pathway. During the inositol phospholipid cycle, PI4-K first catalyzes the phosphorylation of D4 on the inositol phospholipid (PI) ring to generate 4-phosphate Phosphatidylinositol (4-phosphatidyl-inositide, PIP) is further catalyzed by PIP5-K kinase to synthesize (4,5-phosphatidyl-inosididediphosphate, PIP2); PIP2 is hydrolyzed under the action of phospholipase C (Phospholipase C, PLC) to Inositol triphosphate (1,4,5-trisphosphoin...

Claims

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Application Information

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IPC IPC(8): A61K31/381A61P35/00A61P33/06A61P25/28A61P3/10
Inventor 陈畅罗成蒋华良李江美高振赵丹张伦峰乔新华
Owner INSITUTE OF BIOPHYSICS CHINESE ACADEMY OF SCIENCES
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