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Application of compound in preparing anti-mammary cancer medicament aiming at CCL (CC chemokine ligand) 18 target

An anti-breast cancer, compound technology, applied in the direction of anti-tumor drugs, drug combinations, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2012-01-18
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current targeted tumor therapy drugs mainly target tumor cells, but in-depth basic research has shown that the tumor microenvironment plays a key role in the progression of tumors, and there are few targeted drugs targeting the tumor microenvironment; due to the biological characteristics of tumors Variability, many drugs targeting tumor cells are prone to drug resistance. Existing studies have proved that the tumor microenvironment plays a key role in the generation of targeted drug resistance
There are currently no targeted therapies that target cells or chemokines in the tumor microenvironment

Method used

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  • Application of compound in preparing anti-mammary cancer medicament aiming at CCL (CC chemokine ligand) 18 target
  • Application of compound in preparing anti-mammary cancer medicament aiming at CCL (CC chemokine ligand) 18 target
  • Application of compound in preparing anti-mammary cancer medicament aiming at CCL (CC chemokine ligand) 18 target

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: SDS-PAGE experiment of the purified CCL18

[0028] The CCL18 gene encodes a sequence of 89 amino acids, and after the 20 amino acid residues at the amino terminal are excised, the mature protein contains 69 amino acids. The human CCL18 protein can contain 69 amino acids, and there is also a 68 amino acid form (with alanine missing at the carboxy terminus). In previous work, we have cloned, expressed, and purified mature human CCL18, its SDS-PAGE is shown as figure 1 Shown, where band 1 is molecular weight marker; bands 2-7 are CCL18 protein. CCL18 is also commercially available as PeproTech 96-300-34-100ug Recombinant Human MIP-4 (CCL18).

Embodiment 2

[0029] Example 2: Screening Inhibitors from Existing Small Molecule Libraries Using Computer Simulation Molecular Docking

[0030] Subsequently, the three-dimensional space structure of human CCL18 was established by homology modeling method, and the inhibitor was screened from the existing small molecule library by computer simulation molecular docking method. For molecules with higher scores, further use the computer to observe the interaction with amino acids in CCL18, especially the hydrogen bond, the interaction between positive and negative charges, л-лstacking, and the interaction between hydrophobic groups. Then multiple active small molecules are selected to overlap in the binding site to establish a pharmacophore, and then computer docking is carried out on the basis of this pharmacophore to obtain a series of analogs. In the preliminary screening, we obtained 15 compounds with high scores, active multiple small molecules overlapped in the binding site by computer do...

Embodiment 3

[0031] Example 3: Interaction experiment between glycine ester with protective group and protein

[0032] The interaction between glycine esters with protective groups and proteins was further studied by fluorescence chromatography, ITC (isothermal titration calorimetry), CD (circular dichroism), SPR (surface plasmon resonance) and other methods. The binding constant of glycine ester with protective group to CCL18 was measured by SPR method in the range of hundreds of nanomoles. There are multiple amino acids with fluorescent group side chains in the protein sequence of CCL18 (including W=Tryptophan tryptophan, Y=Tyrosine tyrosine), among which there are multiple binding sites between CCL18 and compounds, so through the fluorescence spectrum The conformational change of CCL18 before and after binding the compound can be compared. Fluorescence chromatographic titration changes of glycine ester with protective group and CCL18 protein as follows image 3 shown. The above exper...

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Abstract

The invention provides application of a compound in preparing an anti-mammary cancer medicament aiming at CCL (CC chemokine ligand)18 target. The compound is glycinate with protection radical and can be used as the anti-mammary cancer medicament aiming at the CCL18 target. The structural formula of the compound is shown as formula I. The invention also provides an anti-mammary cancer medicament, wherein the medicament contains effective dose of a compound with a structural formula shown in the formula I. The invention provides the application of the glycinate compound with protection radical shown as the formula I aiming at the CCL18 target in preparing the anti-mammary cancer medicament, and provides a new medicament for treating the mammary cancer.

Description

technical field [0001] The present invention relates to the application of a compound targeting CCL18 in the preparation of anti-breast cancer drugs, in particular to the application of a glycine ester with a protective group as an anti-breast cancer drug targeting CCL18. Background technique [0002] There are a variety of metastasis-related stromal cells in the tumor microenvironment, and a large number of clinical studies have proved that tumor-associated macrophages (TAMs) can promote the invasion and migration of various tumors, including breast cancer. A large number of studies have proved that TAM promotes the invasion and metastasis of breast cancer by secreting chemokines, inflammatory factors and growth factors. However, the currently studied cytokines that promote tumor progression, such as EGF, VEGF, and MMP7 / 9, are not only derived from TAM, but also from tumor cells or other stromal cells. There is no research report on cytokines that only originate from TAM to...

Claims

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Application Information

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IPC IPC(8): A61K31/4015A61P35/00C07D207/46
Inventor 李丁宋尔卫陈静琦刘玉洁黄志纾古练权
Owner SUN YAT SEN UNIV
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