Applications of 8-hydroxyquinoline drugs or salts thereof in preparation of drugs for treatment of diseases associated with BRD4

A technology of hydroxyquinoline and disease, which is applied in the field of medicine and can solve problems that have not been reported in biology or chemotherapeutic drugs

Active Publication Date: 2019-01-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, there have been no reports on biological or chemotherapeutic drugs designed for the binding mechanism of BRD4

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Virtual screening process

[0045] (1) Protein model preparation. Download the crystal structure of BRD4BD1 and inhibitor complex from Protein Data Bank, and use Pymol software to delete the non-aqueous solvent molecules in the crystal structure. Then use the "Protein Preparation Wizard" module in the Schrödinger software to complete a series of protein preparations, including hydrogenation, repairing missing residues, and energy optimization. After the protein is prepared, the non-conserved water molecules are removed. Finally, the inhibitor in the complex was selected as the "reference ligand", and the docking pocket grid file was generated using the Receptor Grid Generation program in the Glide 5.6 software.

[0046] (2) Ligand preparation. The structures of about 1,600 compounds were obtained from the database of small molecule drugs on the market, and then the three-dimensional structure, tautomer, etc. of each small molecule were generated by using th...

Embodiment 2

[0052] Compound screening and experimental verification targeting BRD4 molecular level.

[0053] By constructing a prokaryotic expression system, we successfully expressed and purified the BRD4 protein containing the BD1 domain, using the 5-, 8-, 12-, and 16-position acetylated H4 polypeptide as a substrate, and with the help of amplified chemiluminescence affinity Homogeneous detection (ALPHA) technology successfully established a screening platform targeting the BRD4BD1 domain. When no compound affects the binding of BRD4_BD1 to the substrate polypeptide, ALPHA can detect the maximum signal value, and when the small molecule inhibits the binding of BRD4_BD1 to the substrate polypeptide, the signal value will become weaker. Therefore, when the concentration of the compound gradually decreases from high to low, the signal value will gradually change from low to high, showing an S-shaped curve, which is used to fit and calculate the IC 50 value.

[0054] At the same time, we ...

Embodiment 3

[0059] Inhibition of proliferation, activation of differentiation-related target genes and induction of apoptosis by Nitroxoline in NUT-midline cancer cells.

[0060] First, using two NUT-midline cancer cell lines 797 and per433 as cell models, the IC of the compound Nitroxoline on the proliferation of the two cell lines was investigated. 50 . DMEM / F12 medium was added with 10% fetal bovine serum, cultured with double antibodies, digested with trypsin and passaged. After about 70% of cell confluence, trypsinize, make cell suspension, count cells under microscope, and then inoculate in 96-well plate, 6 plates per well, 1 cell per well. After the cells adhered to the wall, they were treated with Nitroxoline, with a concentration gradient of 100 μM as the initial concentration, and two-fold serial dilution. The change of cell proliferation after administration was detected by Alrma blue method for 72 hours. Take the cell survival rate as the ordinate and the drug concentration...

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Abstract

The present invention relates to applications of 8-hydroxyquinoline (8-OH-quinoline) compounds or salts thereof in preparation of drugs for treatment of diseases associated with BRD4, wherein the diseases associated with BRD4 comprise NUT-midline carcinoma, acute lymphatic leukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma, hepatocellular carcinoma, triple negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, neuroblastoma and other tumor types, and heart failures such as cardiac hypertrophy and cardiomyocyte hypertrophy.

Description

technical field [0001] The invention belongs to the technical field of medicine. Specifically relate to the application of 8-hydroxyquinoline (8-OH-quinoline) compounds or their salts in the preparation of medicines for the treatment of diseases related to BRD4, more specifically, relate to 8-hydroxyquinoline (8-OH-quinoline) quinoline) compounds or salts thereof are used in the preparation for the treatment of NUT-middle line cancer, acute lymphoblastic leukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma, hepatocellular carcinoma, triple negative breast cancer, non-small cell lung cancer, prostate Cancer, pancreatic cancer, neuroblastoma and many other tumor types, as well as in the drug application of heart failure. Background technique [0002] In recent years, Bromodomain-containing protein 4 (BRD4) has been found to be closely related to heart failure. BRD4 inhibitors can alleviate the symptoms of cardiomyocyte hypertrophy by reducing the expression ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61K31/4704A61P9/04A61P35/00A61P35/02
CPCA61K31/47A61K31/4704
Inventor 罗成郑明月谢轶谦邢婧张元元蒋昊王晨陈凯先蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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