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Antitumor agent for thyroid cancer

a thyroid cancer and anti-thyroid cancer technology, applied in the field of anti-thyroid cancer anti-thyroid agents, can solve the problems of no reports

Inactive Publication Date: 2009-08-20
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024]The present invention was achieved regarding the circumstances described above and the problems to be solved by the invention are to provide a therapeutic agent and a method for treating at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract as well as thyroid carcinoma, and to provide a pharmaceutical composition and a therapeutic method highly effective for organisms including cells expressing mutant RET. Another problem to be solved by the invention is to provide an RET kinase inhibitor. Yet another problem to be solved by the invention is to provide a method for predicting the effect of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof.
[0025]In order to solve the above-mentioned problems, the present inventors have gone through keen research and found that 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide has RET kinase-inhibiting activity and that 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof are highly effective against at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract as well as thyroid carcinoma. The present inventors have also found that 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof are highly effective for organisms including cells expressing mutant RET and further found that the effect of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof can be predicted using the presence or the absence of RET mutation in the cell as an indication.
[0086]Since the method according to the invention enables one to predict the effect of the compound without administering the compound to the patient, it has become possible to select a patient who is expected to be more susceptible to the compound. Thus, contribution to the patient's QOL has become possible.

Problems solved by technology

However, none has reported as to what 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof have RET kinase-inhibiting activity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Determination of RET Kinase-Inhibiting Activity of RET Kinase Inhibiting Substance

[0347]RET kinase-inhibiting activity of test substances were tested by ProQinase (Freiburg, Germany, GmbH) upon our request. To be more precise, RET kinase-inhibiting activity was determined as follows.

[0348]1. Expression and Purification of RET

[0349]RET was expressed as human recombinant GST fusion protein (hereinafter, also referred to as “RET recombinant protein”) in an insect cell (Spodoptera frugiperda 9 (Sf9)) according to the method of Baculovirus Expression System. The expressed RET recombinant protein was purified by affinity chromatography using GSH-agarose (Sigma) or Ni-NTH-agarose (Qiagen). The purity and identification of the protein can be confirmed by SDS-PAGE silver staining and western blotting using an antibody specific to RET.

[0350]2. Determination of Inhibitory Activity to RET Kinase Activity

[0351]First, to each well of streptavidin-coated 96-well FlashPlate (Perkin Elmer / NEM), 20 μ...

example 2

Effect of RET Kinase Inhibiting Substance on Ligand-Independent RET Phosphorylation in Human Medullary Thyroid Carcinoma Cell Line (TT)

[0363]1. Preparation of Cell Extract

[0364]Human medullary thyroid carcinoma cell line (TT, purchased from ATCC) was suspended in RPMI1640 medium containing 15% FBS (purchased from Sigma). TT is a cell expressing RET where cysteine at codon 634 in the wild-type RET amino acid sequence is mutated with tryptophan (Biochemical and Biophysical Research Communications, 207, 1022-1028, 1995). Two mL of this cell suspension per well (4×105 cells / mL) was added to 6-well cell culture plate (purchased from FALCON), and cultured in a 5% CO2 incubator (37° C.) overnight. After cultivation, supernatant was removed from each well and 1.8 mL of RPMI1640 medium containing 15% FBS was added. Then, 0.2 mL of test substance 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (methanesulfonate) (diluted in RPMI1640 medium containing 15%...

example 3

Effect of RET Kinase Inhibiting Substance on Cell Growth of Human Medullary Thyroid Carcinoma Cell Line (TT)

[0369]Human medullary thyroid carcinoma cell line (TT, purchased from ATCC) was suspended in RPMI1640 medium containing 15% FBS (purchased from Sigma). 0.1 mL per well of this cell suspension (3×104 cells / mL) was added to 96-well cell culture plate (purchased from NUNC), and cultured in a 5% CO2 incubator (37° C.) overnight. After cultivation, 0.1 mL of test substance 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (methanesulfonate) diluted in RPMI1640 medium containing 15% FBS was added to each well and further cultured in a 5% CO2 incubator (37° C.) for 10 days. After cultivation, 10 μL of Cell Counting Kit-1 (purchased from DOJINDO) was added to each well, treated in 5% CO2 incubator (37° C.) for color development and absorbance of each well was determined with plate reader MTP-500 (Corona Electric) at measurement wavelength of 415 nm...

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Abstract

The objective of the present invention is to provide a pharmaceutical composition and a therapeutic method that are specifically effective against at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract.4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof are specifically effective against at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia and mucosal neuromas of the gastrointestinal tract.

Description

CROSS REFERENCE TO PRIOR RELATED APPLICATIONS[0001]This application is a U.S. national phase application under 35 U.S.C. § 371 of International Patent Application No. PCT / JP2007 / 060560, filed on May 17, 2007, and claims the benefit of U.S. Provisional Patent Application No. 60 / 747,570, filed on May 18, 2006, both of which are incorporated by reference herein. The International Application was published in Japanese on Nov. 29, 2007, as International Publication No. WO 2007 / 136103 A1 under PCT Article 21(2).FIELD OF THE INVENTION[0002]The present invention relates to a therapeutic agent and a method containing a substance that inhibits RET kinase activity (hereinafter, also referred to as an “RET kinase inhibiting substance”) for treating at least one disease selected from multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/47C07D215/00C12Q1/48C12Q1/68G01N33/573
CPCA61K31/47C12Q2600/106C12Q1/6886C07D215/22A61P1/00A61P35/00A61P43/00A61P5/18
Inventor MATSUI, JUNJI
Owner EISIA R&D MANAGEMENT CO LTD
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