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Application of compound T521 or analogues thereof in preparation of antitumor drug

A technology of similar structures and compounds, which is applied in the application field of compound T521 or its structural analogs to prepare anti-tumor drugs, and can solve problems such as restricted directional design

Active Publication Date: 2015-11-11
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of these small-molecule inhibitors with limited quantity and structure are natural products, which greatly limits the structure-based design of small-molecule inhibitors targeting Plk1PBD

Method used

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  • Application of compound T521 or analogues thereof in preparation of antitumor drug
  • Application of compound T521 or analogues thereof in preparation of antitumor drug
  • Application of compound T521 or analogues thereof in preparation of antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1. Culture of cells

[0054] Human osteosarcoma cell MG63, human osteosarcoma cell SaOS-2, human osteosarcoma cell U-2OS, human bone marrow neuroblastoma cell SH-SY5Y, human breast cancer cell MCF-7, human cervical cancer cell HeLa, human Colon cancer cell HCT-116, human colon cancer cell HT-29, human liver cancer cell HepG2, human liver cancer cell Bel7402, human prostate cancer PC3, human lung cancer A459, human embryonic lung fibroblast MRC-5, human embryonic kidney cell HEK- 293, human hepatocyte L02, all cells are adherent cells, passaged once every 48 hours. After the cells are full, discard the old medium, rinse the cells with PBS and discard, then add an appropriate amount of trypsin, digest at room temperature for about 2-10min, discard the digestion solution, and immediately add the medium containing 10% FBS to Inhibit the activity of trypsin, gently tap the cells in the culture flask repeatedly with an elbow pipette, so that the cells are completely ...

Embodiment 2

[0055] Example 2 Determination of Compound T521's Inhibitory Activity to PLK1PBD

[0056] The activity assay adopts the fluorescence polarization (FP) high-throughput screening model to measure the activity of the compound.

[0057] Measuring principle:

[0058] It is mainly based on the principle that the polarization of fluorescent molecules is closely related to the rotation speed of fluorescent molecules when they are excited. When a fluorescent molecule is excited by plane polarized light, if the fluorescent molecule remains stationary while being excited, the emitted light will be in the same polarization plane; if the fluorescent molecule is kept rotating while being excited, the emitted light will be in the same polarization plane as the excited light. Different planes of polarization. If fluorescein is excited with vertically polarized light, the intensity of emitted light can be detected in the vertical and horizontal polarization planes (the degree to which the em...

Embodiment 3

[0068] Example 3 Competitive ELISA experiment mediated by compound T521 on Wee1A phosphorylated polypeptide

[0069] The activity was determined by competition ELISA experiment mediated by Wee1A phosphorylated polypeptide.

[0070] Measuring principle:

[0071] Wee1APhosphopeptide (C-EEEGFGSSpSPVKSPAAP-OH) is a synthetic Plk1PBD substrate Wee1 phosphorylation mimic peptide (SpSmotif), which can specifically bind to Plk1PBD protein. The Cysteine ​​sulfhydryl group in Wee1APeptide can covalently react with the maleimide group on the surface of a 96-well plate, thereby immobilizing biomacromolecules or polypeptides containing sulfhydryl groups.

[0072] test methods:

[0073] Coat the plate with 100 μL / well of 4 μM Wee1APeptide and incubate at 37°C for 2 hours; wash 3 times with PBST, 2 minutes each; add 200 μL / well BlockingBuffer to seal, 37°C for 2 hours; Small molecule compound T521 with concentrations of 400 μM, 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.13 μM, and ...

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Abstract

The invention relates to the application of a compound T521 or analogues thereof in the preparation of an antitumor drug, the application is on the basis of combining the compound T521 or the analogue of the compound T521 with Plk1 (Polo-like kinases1) PBD (Polo Box Domain), so that the function that the Plk1 is combined with a nature-ligand thereof is inhibited. The invention also relates to a screening method of a Plk1 inhibitor taking a key amino acid space structure as a target in a Plk1 PBD active center.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and in particular relates to the application of compound T521 or its structural analogues in the preparation of antitumor drugs. Background technique [0002] Cancer is a large class of diseases characterized by abnormal cell proliferation and metastasis, and its pathogenesis is closely related to harmful environmental factors, unhealthy lifestyle and genetic susceptibility. In 2000, there were about 10 million new cancer cases worldwide, 6.2 million deaths, and 22 million existing cases [1] . It is estimated that in 2020, there will be 15 million new cancer cases, 10 million deaths, and 30 million existing cases [1] . Cancer is becoming the first killer of human beings in the new century. With the aging of the population, the destruction of the ecological environment, the emergence of unhealthy lifestyles and food safety issues, the incidence of malignant tumors in my country has ...

Claims

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Application Information

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IPC IPC(8): A61K31/421A61K31/192A61P35/00
Inventor 司书毅陈云雨张晶王彦昶蒋建东李妍李东升
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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