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Polycyclic inhibitor of anaplastic lymphoma kinase

a polycyclic inhibitor and lymphoma kinase technology, applied in the field of polycyclic inhibitors of anaplastic lymphoma kinase, can solve the problems of malignant cell transformation, high expression and over-activation of fusion proteins having alk kinase activity,

Active Publication Date: 2018-03-29
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The purpose of the patent text is to explain the technical solutions and advantages of the invention in a clear and complete way. The examples provided in the text are a part of the invention and other examples can be obtained by a person skilled in the art without paying creative work. The technical effects of the invention are not clearly explained in this text.

Problems solved by technology

The analysis of these fusion genes shows that they all comprise a 3′ terminal gene sequence of ALK gene, which encodes an intracellular kinase domain; and the gene fragments fused to ALK all comprise a promoter element and encode a sequence that mediates self-dimerization, thus resulting in high expression and over-activation of the fusion protein having ALK kinase activity, and causing malignant transformation of cell.

Method used

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  • Polycyclic inhibitor of anaplastic lymphoma kinase
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  • Polycyclic inhibitor of anaplastic lymphoma kinase

Examples

Experimental program
Comparison scheme
Effect test

experimental example 1

Assay on In Vitro ALK Kinase-Inhibiting Activity of the Compounds Provided in Examples of the Invention

[0171]Test compounds: Compounds 1, 2, 3 and 4provided in Examples of the invention, the chemical names and preparation methods of which can be found in the preparation examples.

[0172]Control agent: Ceritinib, lab-made (prepared by reference to the method in Publication WO2008 / 073687A2).

[0173]Experimental Method

[0174]Preparation of ALK Kinase Buffer: A suitable amount of a stock solution of MgCl2 at a concentration of 1000 mM, a suitable amount of a stock solution of SEB at a concentration of 2500 nM, a suitable amount of a stock solution of DTT at a concentration of 100 mM, and a suitable amount of 5×enzyme buffer were added to ultrapure water to reach a final concentration of: 5 mM, 25 nM, 1 mM, and 1×enzyme buffer, respectively. The resultant mixture was mixed homogeneously, for later usage.

[0175]Preparation of 2.5×Test Compound Colutions:

[0176]Preparation of a stock solution of ...

experimental example 2

Assay on In Vitro ALK Kinase-Inhibiting Activity of the Compounds Provided in Examples of the Invention

[0190]Test compounds: Compounds 5, 6 and 8 provided in Examples of the invention, the chemical names and preparation methods of which can be found in the preparation examples.

[0191]Control agent: Ceritinib, lab-made (prepared by reference to the method in Publication WO2008 / 073687A2).

[0192]Experimental method: Measurement of ALK kinase inhibitory activity by Caliper Mobility Shift assay.

[0193]1. Preparation of 1-Fold Kinase Buffer

[0194]To pH7.5HEPES, Brij-35 at a concentration of 30%, a stock solution of MgCl2 at a concentration of 1M, and a stock solution of DTT at a concentration of 1M, ultrapure water was added and mixed homogeneously until HEPES was at a final concentration of 50 mM, Brij-35 was at a final concentration of 0.0015%, MgCl2 was at a final concentration of 10 mM, and DTT was at a final concentration of 2 mM.

[0195]2. Preparation of Stop Solution

[0196]To a stock solu...

experimental example 4

Assay on In Vitro Cell Activity of the Compounds Provided in Examples of the Invention

[0231]Test compounds: Compounds 1-6 and 8 provided in Examples of the invention, the chemical names and preparation methods of which can be found in the preparation examples.

[0232]Control agent: Ceritinib, lab-made (prepared by reference to the method in Publication WO2008 / 073687A2), the formula of which is shown in the Background.

[0233]The meanings of abbreviations in the following experiments are described as follows.

[0234]rpm: revolutions per min;

[0235]DMSO: dimethyl sulfoxide;

[0236]MTS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide;

[0237]RPMI1640: 1640 medium (RPMI: Roswell Park Memorial Institute);

[0238]“×” in 500×, 1000×, 10×: fold.

[0239]Experimental Method

[0240](I)NCI-H3122, Karpas-299cell:

[0241](1) Cell Preparation:

[0242]The cells were cultured to a fusion degree of 80% in RPMI-1640 medium containing 10% fetal bovine serum, 100 U / ml penicillin and 100 mg / ml streptomycin, i...

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PUM

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Abstract

Disclosed is a polycyclic inhibitor of anaplastic lymphoma kinase as represented by Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. Also disclosed is a method for preparing the compound, a pharmaceutical preparation and a pharmaceutical composition comprising the compound, and use of the compound, the pharmaceutically acceptable salt or stereoisomer thereof in manufacture of a medicament for the treatment and / or prevention of, for example, an anaplastic lymphoma kinase-mediated cancer or non-cancer related diseases.

Description

TECHNICAL FIELD[0001]The invention relates to a polycyclic inhibitor of anaplastic lymphoma kinase, or a pharmaceutically acceptable salt or a stereoisomer thereof, a method for preparing the compound, a pharmaceutical preparation and a pharmaceutical composition comprising the compound, and use of the compound, or a pharmaceutically acceptable salt or stereoisomer thereof in manufacture of a medicament for the treatment and / or prevention of an anaplastic lymphoma kinase-mediated cancer or non-cancer related diseases.BACKGROUND ART[0002]Anaplastic lymphoma kinase (ALK) is a member of receptor tyrosine kinase family, which can recruit downstream protein by autophosphorylation, and further modulate cell metabolism and growth by expression of a specific gene. Anaplastic lymphoma kinase was first found in Anaplastic large cell lymphoma (ALCL), and was also found later to be expressed in a high level in non-small cell lung cancer (NSCLC).[0003]The abnormal expression of ALK in some ALCL / ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D405/14A61K31/506
CPCC07D405/14A61K31/506A61P13/08A61P17/00A61P35/00A61P35/02A61P43/00A61K31/517A61K31/7068
Inventor WU, FRANK
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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