2-(quinazoline-4-amino)-5-thiazole carboxamide derivatives and biological medicine use thereof

A technology of thiazole carboxamide and quinazoline, applied in the field of biopharmaceuticals, can solve the problems of difficult to overcome tumor drug resistance, low structural diversity, etc.

Inactive Publication Date: 2014-05-14
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the described compounds still have the following defects: for example, the structural diversity is not high, and it is difficult to overcome the problem of drug resistance of tumors, etc.

Method used

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  • 2-(quinazoline-4-amino)-5-thiazole carboxamide derivatives and biological medicine use thereof
  • 2-(quinazoline-4-amino)-5-thiazole carboxamide derivatives and biological medicine use thereof
  • 2-(quinazoline-4-amino)-5-thiazole carboxamide derivatives and biological medicine use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Virtual screening based on DOCK program and GOLD program

[0019] The crystal structure of Src kinase is taken from the Protein Data Bank protein database (PDB Code: 2H8H)

[0020] , And use the Chimera program to preprocess the complex crystal structure, that is, delete saracatinib and water molecules, and add hydrogen atoms. The active pocket of Src kinase is defined as around saracatinib Space within.

[0021] The main steps of virtual screening include:

[0022] 1) Screen the known chemical database Enamine with the GOLD program, and use the scoring function E int =E vdw +E elec (E int : Ligand-receptor interaction energy; E vdw : Van der Waals action energy; Eelec: electrostatic action energy to score the screening results;

[0023] 2) Select the top 500 compounds in the score;

[0024] 3) Use the more accurate scoring function GOLD Score in the GOLD program to re-evaluate the preliminary screening results of DOCK; 4) Select compounds with a GOLD Score great...

Embodiment 2

[0025] Example 2 Biological Activity Test

[0026] Select candidate compounds from the Enamine small molecule database (http: / / www.asinex.com), purchase them, and conduct activity tests.

[0027] The selected compounds were tested for their inhibition of Src kinase activity by Electrophoretic Mobility Shift Assay (EMSA), and the experiment was performed on a 384-well plate. The positive control substance of Src kinase inhibitor is Staurosporine. Both the test drug and the positive drug are dissolved in DMSO and mixed with kinase buffer (20mM HEPES, pH 7.5, 0.01% Triton X-100, 5mM MnCl2, 2mM DTT), and shaken Mix for 10 minutes on the vessel, then add Src kinase to the well and incubate for 10 minutes at room temperature. The phosphoacceptor peptide FAM-P4 and ATP containing tyrosine were added to the wells to finally obtain an enzyme reaction system of 25uL / well, and incubated at 28°C for 60min. At the end of the incubation, add 25uL of stop buffer (100mM HEPES, pH 7.5, 0.015% Bri...

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Abstract

The invention belongs to the field of biopharmacy and relates to 2-(quinazoline-4-amino)-5-thiazole carboxamide derivatives and a biological medicine use thereof. Based on a crystal structure of a compound of high-quality Src receptor tyrosine kinase and a Src receptor tyrosine kinase inhibitor saracatinib, a Src active pocket is defined, and a searching process is carried out on a known chemical storage by high-speed virtual screening software DOCK and an accurate scoring function so that the 2-(quinazoline-4-amino)-5-thiazole carboxamide small-molecular compounds having high inhibition activity to Src are obtained. A biological activity test proves that the 2-(quinazoline-4-amino)-5-thiazole carboxamide small-molecular compounds have strong inhibition activity to Src receptor tyrosine kinase, can be used for preparing antitumor drugs especially such as a drug for resisting Src kinase signal transduction system adjustment disorder-caused tumors, can be used as drug lead compounds for synthesis of a novel Src kinases inhibitor and especially can be used for treating Src-related tumor diseases.

Description

Technical field [0001] The present invention belongs to the field of biopharmaceuticals, and relates to 2-(quinazoline-4-amino)-5-thiazolecarboxamide derivatives and their biopharmaceutical uses. The compound has a strong inhibitory effect on Src receptor tyrosine kinase Function, can prepare anti-tumor drugs, especially in the treatment of Src-related tumor diseases. Background technique [0002] The prior art discloses that the expression product of the Src gene, Src protein, is a tyrosine kinase. This gene is the first oncogene to be discovered. Its main function is to catalyze the phosphorylation of tyrosine residues of downstream signaling proteins. Activate the signal transduction pathway. The Src was originally found to exist in the Rous sarcoma retrovirus (retrovirus Rous sarcoma virus), and subsequent studies have found that there is a highly homologous c-Src protein kinase in cells. In addition, recent studies have shown that Src kinase overexpression is related to th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61K31/517A61P35/00A61P35/02
CPCC07D417/12
Inventor 付伟李变古险峰
Owner FUDAN UNIV
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