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SH2 domain binding inhibitors

a technology of sh2 domain and inhibitor, which is applied in the field of macrocyclic peptides, can solve the problems of high affinity binding loss, suffering and possibly death,

Inactive Publication Date: 2005-06-02
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] The present invention provides SH2 domain binding inhibiting compounds or a pharmaceutically acceptable salt or stereoisomer(s) thereof. The compounds of the present invention have an advantage that their conformation is constrained to provide attractive binding affinity with a SH2 domain protein.

Problems solved by technology

These diseases or disorders affect a large portion of the population, leading to suffering and possibly death.
These arginine-phosphate interactions are related to the overall binding, such that high affinity binding is usually lost by removal of the phosphate group.

Method used

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Examples

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example 1

[0060] This Example illustrates methods of preparing compounds in accordance with an embodiment of the present invention. The methods are illustrated schematically in FIGS. 1-6.

[0061] Compounds 5-6 are prepared as shown in FIGS. 1A-B.

[0062] (4S)-3-[3-(5-methylindolyl)propanoyl]-4-phenyl-1,3-oxazolidin-2-one (8). To the suspension of (4S)-4-phenyl-1,3-oxazolidin-2-one (6.85 g, 42 mmol) in anhydrous THF (130 mL) was added BuLi (26.3 mL, 42 mmol) at −78° C. and the mixture was stirred under argon (0.5 h). To the above suspension was added a solution of active ester prepared by reacting 3-(5-methylindolyl)propanoic acid 7 (10.23 g, 50.39 mmol) in anhydrous THF (130 mL) and trimethylacetyl chloride (5.10 g, 50.39 mmol) in the presence of N-methyl morphine (6.06 g, 50.39 mmol) at 0° C. under argon, followed by stirring at −78° C. (1 h). The combined reaction mixture was stirred at −78° C. for an additional 2 h, then the solution was warmed to room temperature and stirred overnight. The ...

example 2

[0116] This example illustrates some of the properties of compounds in accordance with an embodiment of the invention.

[0117] Binding affinities were determined as follows. Surface Plasmon Resonance (SPR) Determination of Grb2 SH2 Domain-Binding Kd Values. Binding experiments were performed on a BIACORE S51 instrument (Biacore Inc., Piscataway N.J.). All Biotinylated Grb2 SH2 domain protein (b-Grb2) was expressed and purified (Protein Expression Laboratory and The Protein Chemistry Laboratory, SAIC-Frederick). The b-Grb2 was immobilized onto carboxymethyl 5′ dextran surface (CM5 sensor chip, Biacore Inc.) by amine coupling. The lyophilized b-Grb2 was reconstituted in fifty percent DMSO in H2O to make a stock solution of 1 mg / mL and stored at −80° C. A 1:12.5 dilution of b-Grb2 was used for immobilization and prepared by dilution in acetate buffer pH-5.0, with 5% DMSO. 1×PBS (phosphate buffered saline, pH 7.4) was used as the running buffer.

[0118] An immobilization wizard was used t...

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Abstract

Disclosed are compounds represented by the formula: or a pharmaceutically acceptable salt or isomer thereof, wherein R1-R6 are as defined in the specification. These compounds are targeted for use as inhibitors of SH2 domain binding with a phosphoprotein, and are contemplated for use in a number of diseases including cancer. Also disclosed are pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO A RELATED PATENT APPLICATION [0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 60 / 504,241, filed Sep. 18, 2003.FIELD OF THE INVENTION [0002] This invention relates to macrocyclic peptides, a composition comprising such macrocyclic peptides, and a method of using the peptides, e.g., in inhibiting SH2 domain binding with a phosphoprotein such as in the prevention or treatment of a disease, state, or condition in a mammal. BACKGROUND OF THE INVENTION [0003] The pharmaceutical industry is in search for new classes of compounds for the therapy and prophylaxis of proliferative diseases such as cancer, autoimmune diseases, and hyperproliferative skin disorders such as psoriasis. These diseases or disorders affect a large portion of the population, leading to suffering and possibly death. [0004] Some of these diseases or disorders may involve signal transduction. Signal transduction is found in normal cellular homeostasis and is ...

Claims

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Application Information

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IPC IPC(8): A61K38/00C07K5/02C07K5/065
CPCA61K38/00C07K5/06078C07K5/021
Inventor BURKE, TERRENCE R. JR.SHI, ZHEN-DANKANG, SANG-UK
Owner UNITED STATES OF AMERICA
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