Selective inhibitors that interfere with the interaction of fibroblast growth factor receptor and Frs2 for the prevention and treatment of cancer and other diseases

A technology selected from, pharmaceutically acceptable salts, applied in the field of selective inhibitors that interfere with the interaction of fibroblast growth factor receptor and FRS2 for the prevention and treatment of cancer and other diseases, which can solve the weak effect of FRS2, reduced efficiency, problems such as increased toxicity

Active Publication Date: 2019-06-04
LIMITED LIABILITY COMPANY RUSSIAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, simultaneous blockade of several types of FGFR is unnecessary and may result in not only increased toxicity but also reduced efficacy
Numerous works have shown that existing low-molecular-weight inhibitors of tyrosine kinases at nanomolecular concentrations inhibit the intracellular tyrosine kinase activity of FGFR, yet have weak effects on the phosphorylation (activity) of FRS2
In other words, the interaction between FGFR and FRS2 appears to be important even when the activity of FGFR's intracellular tyrosine kinase is inhibited, and its absence may be a factor in resistance

Method used

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  • Selective inhibitors that interfere with the interaction of fibroblast growth factor receptor and Frs2 for the prevention and treatment of cancer and other diseases
  • Selective inhibitors that interfere with the interaction of fibroblast growth factor receptor and Frs2 for the prevention and treatment of cancer and other diseases
  • Selective inhibitors that interfere with the interaction of fibroblast growth factor receptor and Frs2 for the prevention and treatment of cancer and other diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1 (research results): Interference with FGFR2 and FRS2 interaction when inhibitor RPT835 is added

[0075] In order to evaluate the effect of the RPT835 inhibitor characterized by formula II of the present invention, gastric cancer cell KATO III expressing FGFR2 was used for FRS2 phosphorylation. FGFR was stimulated by adding FGF-2 at a concentration of 1 mg / mL and heparin at 10 mg / mL to the cells. RPT835 was added at various concentrations. A portion of the cells was left without the addition of the inhibitor, and a portion of the cells—without the addition of the inhibitor, or stimulator (control group).

[0076] Two standard methods for assessing the level of phosphorylation of FGFR and FRS2:

[0077] - Western blotting using manual work;

[0078] - Use automatic system Wes TM (ProteinSimple; Santa Clara, CA) automated capillary electrophoresis and immunodetection.

[0079] Stimulation of KATO III cells with fibroblast growth factor resulted in significa...

Embodiment 2

[0082] Example 2 (research results): RPT835 inhibitors do not affect the tyrosine kinase activity of FGFR.

[0083] The previous examples demonstrated the lack of effect of the inhibitor RPT835 on the phosphorylation of FGFR. In the present study, to disprove the mechanism of action of RPT835 as a tyrosine kinase inhibitor, the levels of common FGFR and phospho-FGF were evaluated before and after the addition of RPT835.

[0084] As in Example 1, gastric cancer cell KATO III, which strongly expresses FGFR2, was used. A portion of the cells was stimulated with FGF-2 at concentrations of 1 mg / mL and heparin at 10 mg / mL. Another portion of cells was left unstimulated. Inhibitor RPT835 was added to the cells at doses of 1, 10, 100, 1000 nM. A control group was kept without adding RPT835.

[0085] Using automated systems with immunoassays and using Wes TM (ProteinSimple; Santa Clara, CA) standard immunoblotting and automated capillary electrophoresis to assess the level of FGFR...

Embodiment 3

[0087] Example 3 (research results): Inhibitor RPT835 does not inhibit the binding of FGF-2 and FGFR2

[0088] A non-radioactive enzyme-linked FGF2 binding assay test was performed to evaluate whether RPT835 affects the binding of FGFR2 and ligand (FGF-2). In the binding assay of FGF-2, a recombinant chimeric protein FGFR2-Fc consisting of the human extracellular domain FGFR2α(IIIc) and the Fc fragment of human IgG1 was used. FGFR2α contains all 3 immunoglobulin-like domains and represents domain IIIс FGFR2 with high affinity for FGF-2. A 96-well plate was coated with FGFR2-Fc protein, and the following were added to the wells:

[0089] 1) FGF-2 only

[0090] 2) FGF-2+heparin

[0091] 3) Various concentrations of inhibitor RPT835+FGF-2+heparin

[0092] 4) A part of the wells retain no stimulator (FGF-2+heparin) and RPT835 (negative control).

[0093]After incubation, ELISA test using the corresponding antibody and subsequent determination of OD 650 (optical density at a ...

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Abstract

The present invention relates to medicaments and includes the use of inhibitors that selectively interfere with the interaction between the fibroblast growth factor receptor and FRS2, and with other components of the FRS2 complex. Compared to other inhibitors and monoclonal antibodies, the use of the selective inhibitors described in the present invention results in a proven enhancement of anti-tumor efficacy, a reduction in the toxicity of the treatment and the possibility to achieve complete blockade and implement long-term therapy using low dose concentrations . Advantages of the present invention include the development of new classes of medical agents for the treatment of malignancies and other diseases.

Description

Background technique [0001] We know that the development of malignant tumors is based on the hyperproliferation of cells and also the formation of blood vessels in the tumor through which it is fed (angiogenesis) (J. Folkman et al. Nature; 339, 58 (1989)). New blood vessels form from pre-existing endothelium and are an important component of many diseases and conditions including, for example, tumor growth and dissemination, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic retinopathy, lens Postfibroplasia, neovascular glaucoma, hemangiomas, immune rejection of transplanted corneas and other tissues, and chronic inflammation. [0002] The proliferation of tumor cells and endothelial cells can be caused by various factors directly occurring in nature. These factors bind to receptors on the surface of tumors, endothelial cells, and other cells, which leads to activation of the receptors and signaling within the cells with subsequent division. [0003] According to am...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/10A61K31/498A61K31/505A61K31/34A61K31/185A61K31/435A61K31/495A61P35/00
CPCA61K31/4418A61K31/10A61K31/185A61K31/34A61K31/435A61K31/495A61K31/498A61K31/505A61P35/00C07D213/42C07D239/26C07D239/42
Inventor 谢尔盖·阿莱克谢耶夫维奇·休兰丁米哈伊尔·尤维奇·比亚霍夫利亚·瓦列维奇·齐马费约
Owner LIMITED LIABILITY COMPANY RUSSIAN PHARMA TECH
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