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Application of benzamide compound in IAP protein inhibitor and in preparation of anti-tumor drug

A protein inhibitor, benzamide technology, applied in the field of biomedicine, can solve the problems of drug resistance, expensive targeted therapy, lack of targeted drugs, etc., to achieve antigenic response, good antitumor activity, and difficult activity Effect

Active Publication Date: 2020-08-14
SOUTHWEST MEDICAL UNIVERISTY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003]However, due to the high price of targeted therapy, most of them do not have generic drugs, and targeted drugs are still relatively scarce; currently, the targets of marketed tumor-targeted drugs mainly include EGFR , VEGFR-2, HER2, PARP, CDK4 / 6, BCRA1 / 2, MET, c-KIT, mTOR, CTLA4, PD1, etc., but many of the marketed tumor targeting drugs have been clinically resistant

Method used

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  • Application of benzamide compound in IAP protein inhibitor and in preparation of anti-tumor drug
  • Application of benzamide compound in IAP protein inhibitor and in preparation of anti-tumor drug
  • Application of benzamide compound in IAP protein inhibitor and in preparation of anti-tumor drug

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Experimental program
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Effect test

Embodiment 1

[0055] Research on the combination of benzamide compounds of the present invention and IAP protein.

[0056] 1. Molecular docking

[0057] AutoDock Vina software was used for molecular simulation experiments; the structure of benzamide compounds was exported to pdbqt format using AutoDockTools; c-IAP1 and XIAP BIR3 domain crystal structures ( PDB ID: 3UW4) Download from the PDB database; remove all water and solvent molecules; add Gasteiger-Marsili potential to the protein structure, set the docking box size to Coordinates [x, y, z=26.375, -20.547, -47.589], other parameters are set to default; the results are exported from the PyMol online system (www.pymol.org); the exported results are as follows figure 1 as shown, figure 1 Middle: The red area represents the negative potential; the blue represents the positive potential, and the amino acid residues interacting with the benzamide molecules have been marked in the figure, and the dotted line represents the hydrogen bond;...

Embodiment 2

[0063] The benzamide compound of the invention significantly inhibits the growth of human lung cancer cells, human colorectal cancer cells and human breast cancer cells.

[0064] MTT experiment:

[0065] Human tumor cell lines (including lung cancer H460, colorectal cancer HCT116 and HT29, breast cancer MCF-7) were incubated at 37°C, 5% CO 2 , cultured and passaged in RPMI 1640 complete medium (containing inactivated fetal bovine serum 10%, streptomycin 100 μg / mL, penicillin 100 U / mL) under the condition of relative saturated humidity 95%; normal human epithelial cells (lung, cervical ) in conditioned medium (containing F12 basal medium 25%, hydrocortisone 25ng / mL, EGF 0.125ng / mL, amphotericin B 250ng / mL, gentamicin 10μg / mL, cholera toxin 0.1nM, insulin 5 μg / mL, ROCK inhibitor Y-276324 10 μM, and the balance is cultured in DMEM complete medium);

[0066] Take each cell grown in the logarithmic phase, press 3×10 3 The density of cells / well was inoculated in 96-well plates, a...

Embodiment 3

[0069] The benzamide compound of the present invention can significantly induce the apoptosis of human breast cancer MCF-7 cells.

[0070] Cell apoptosis was detected by flow cytometry:

[0071] Take the human breast cancer MCF-7 cells in logarithmic phase growth, press 2×10 5 Cells were seeded in 6-well plates at a density of one per well, and the cells adhered overnight; prepared RPMI1640 complete medium containing 0, 5, 10, 15, and 20 μM of benzamide compounds, and added them to corresponding well plates; 48 hours later, the cells were used After digestion with 0.25% trypsin, centrifuge to remove the supernatant, suspend with PBS, and centrifuge to remove the supernatant (the whole process is light, to reduce damage to the cells, and to remove the supernatant is to avoid absorbing the precipitate as much as possible to reduce the loss of cells); use Annexin V-FITC / PI kit was used to detect apoptosis; add 5 μL Annexin V-FITC to each sample and place in the dark for 10 minut...

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Abstract

The invention relates to an application of a benzamide compound in an IAP protein inhibitor and in preparation of an anti-tumor drug. The compound has a structure as shown in formula I. The benzamidecompound can be combined with IAP protein to inhibit the function of the IAP protein, has high anti-tumor activity, tumor cells can be selectively killed, apoptosis of the tumor cells can be induced and growth of the tumor cells can be inhibited, and the tumor killing effect is achieved.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to the application of a benzamide compound in IAP protein inhibitors and preparation of antitumor drugs. Background technique [0002] At present, many anti-tumor drugs have been developed in China and abroad, but traditional chemotherapeutic drugs such as paclitaxel and cisplatin, while killing tumor cells, will also damage many normal tissues such as bone marrow, digestive tract, liver, kidney, and nervous system. cause damage. Molecular targeted therapy has gradually become the first choice and research hotspot in the field of tumor treatment in China and abroad due to its specificity, strong effectiveness, good patient tolerance, and relatively low toxicity and side effects. [0003] However, due to the high price of targeted therapy, most of them have no generic drugs, and targeted drugs are still relatively scarce; currently, the targets of marketed tumor-targeted drugs m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4375A61P35/00
CPCA61K31/4375A61P35/00
Inventor 吴旭王胜鹏沈晶李明星肖占刚尹建华
Owner SOUTHWEST MEDICAL UNIVERISTY
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