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Agonists of src homology-2 containing protein tyrosine phosphatase-1 and treatment methods using the same

a technology of src homology and tyrosine phosphatase, which is applied in the field of compounds having src homology2 containing, to achieve the effects of reducing the effect of sc-59, and silencing shp-1

Active Publication Date: 2015-07-09
NAT TAIWAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new compounds that can act as SHP-1 agonists and reduce P-STAT3, which are useful for treating certain diseases such as cancer. These compounds do not block the activity of other kinases, such as Raf-1 and VEGFR2, and can be used in pharmaceutical compositions for increasing SHP-1 expression or treating diseases associated with decreased SHP-1 expression.

Problems solved by technology

Loss function of SHP-1 results in osteoclast and eventually leads to osteoporosis.

Method used

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  • Agonists of src homology-2 containing protein tyrosine phosphatase-1 and treatment methods using the same
  • Agonists of src homology-2 containing protein tyrosine phosphatase-1 and treatment methods using the same
  • Agonists of src homology-2 containing protein tyrosine phosphatase-1 and treatment methods using the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Chemical Synthesis

1.1 Materials

[0131]Proton nuclear magnetic resonance (1H-NMR) spectra were recorded on Bruker DPX300 (400 MHz) instruments. Chemical shifts are reported as values (ppm) downfield from internal deuterated Chloroform of the indicated organic solution. Peak multiplicities are expressed as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; ddd, doublet of doublet of doublets; dt, doublet of triplet; brs, broad singlet; m, multiplet. Coupling constants (J values) are given in hertz (Hz). Reaction progress was determined by thin layer chromatography (TLC) analysis on silica gel 60 F254 plate (Merck). Chromatographic purification was carried on silica gel columns 60 (0.063-0.200 mm or 0.040-0.063 mm, Merck), basic silica gel. Commercial reagents and solvents were used without additional purification. Abbreviations are used as follows: CDCl3, deuterated chloroform; DMSO-d6, dimethyl sulfoxide-d6; EtOAc, ethyl acetate; DMF, N,N-dimethylformamid...

example 2

Bioassay

2.1 Materials and Methods

2.1.1. Reagents and Antibodies

[0221]Sorafenib (Nexavar®) was kindly provided by Bayer Pharmaceuticals (West Haven, Conn.). Sodium vanadate and SHP-1 inhibitor were purchased from Cayman Chemical (Ann Arbor, Mich.). Antibodies for immunoblotting such as Raf-1, cylcin D1, and PARP were purchased from Santa Cruz Biotechnology (San Diego, Calif.). Other antibodies such as anti-pVEGFR2 (Y1175), VEGFR2, survivin, phospho-STAT3 (Tyr705), and STAT3 were from Cell Signaling (Danvers, Mass.).

2.1.2. Cell Culture

[0222]The Huh-7 HCC cell line was obtained from the Health Science Research Resources Bank (Osaka, Japan; JCRB0403). The PLC / PRF / 5 (PLC5), Sk-Hep-1, and Hep3B cell lines were obtained from American Type Culture Collection (Manassas, Va.). The cells were maintained in DMEM supplemented with 10% FBS, 100 units / mL penicillin G, 100 μg / mL streptomycin sulfate and 25 μg / mL amphotericin B in a 37° C. humidified incubator in an atmosphere of 5% CO2 in air. Othe...

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Abstract

The present invention provides new compounds of formula I, II or III, which have Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1) agonist activity. Also provided are treatment methods using the compounds of formula I, II or III.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application claims a continuation-in-part of U.S. patent application Ser. No. 14 / 235,620, filed on Jan. 28, 2014, which claims the priority benefit of Provisional Application No. 61 / 514,555, filed on 3 Aug. 2011. The entirety of each of the above-mentioned patent applications is hereby incorporated by reference herein and made a part of this specification.FIELD OF THE INVENTION[0002]The present invention relates to new compounds having Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1) agonist activity and treatment methods using the same.BACKGROUND OF THE INVENTION[0003]SHP-1, a protein-tyrosine phosphatase with two Src homology 2 (SH2) domains, is a regulator of various intracellular signaling molecules, such as signal transducer and activator of transcription 3 (STAT3), KIT, CD22, CD5, CD72, SHPS-1, TIMP (metalloproteinases), CDK2, p27, SRC, ZAP70, IL-10, NF-κB, Lck, 3BP2, Lyn and cyclin D1.[0004]STAT3 is a transcri...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07C311/29C07D215/233C07C255/60C07D213/81C07C275/40C07C255/59
CPCC07D471/04C07C275/40C07C311/29C07D215/233C07C255/60C07D213/81C07C255/59C07C255/54C07C275/24C07C275/30C07C275/36C07C311/21
Inventor SHIAU, CHUNG-WAICHEN, KUEN-FENG
Owner NAT TAIWAN UNIV