CN110818769A - Protein tyrosine phosphatase 2 receptor antagonist and application thereof - Google Patents
Protein tyrosine phosphatase 2 receptor antagonist and application thereof Download PDFInfo
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- CN110818769A CN110818769A CN201911103378.3A CN201911103378A CN110818769A CN 110818769 A CN110818769 A CN 110818769A CN 201911103378 A CN201911103378 A CN 201911103378A CN 110818769 A CN110818769 A CN 110818769A
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- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention provides 3 protein tyrosine phosphatase 2 receptor antagonists and application thereof, and in vitro biological experiments show that the 3 protein tyrosine phosphatase 2 receptor antagonists have protein tyrosine phosphatase 2 receptor antagonistic activity.
Description
Technical Field
The invention belongs to the field of small molecule drugs, and particularly relates to a 3-protein tyrosine phosphatase 2 receptor antagonist and application thereof.
Background
Protein tyrosine phosphatase 2(SHP2) is an intracellular type of protein tyrosine phosphatase. It contains 2 Src homology domains. SHP2 is encoded by the human PTPN11 gene, which contains two N-terminal SH2 domains (N-SH2 and C-SH2), a catalytic domain, and a C-terminal containing tyrosine phosphorylation sites, and a proline-rich group. Each SH2 region in the structure has an independent phosphotyrosine binding site, and the SH2 region is a group containing 100 amino acid residues, plays an important role in regulating the binding of SHP2 and phosphorylated tyrosine residues in other molecules, and further guides the interaction between phosphatase-specific proteins, wherein the interaction is a signal transduction cascade reaction initiated by tyrosine phosphorylation. It has dephosphorizing and pulse exciting effect on other signal molecules inside cell, participates in various signal conducting process and plays important role in human body's growth and development.
SHP2 is widely distributed in various tissues and cells of the body, and SHP2 has been reported to be highly correlated with tumor development and metastasis, and can promote the growth and migration of tumor cells. The activating mutation of SHP2 is found in malignant human tumors, such as lung and colon. Mutations in SHP2 also contribute to a variety of diseases, such as noonan syndrome, LEOPARD syndrome. Studies have shown that SHP2 acts to promote lymphoma cell proliferation, invasion and inhibit apoptosis in diffuse large B-cell lymphoma transformation, presumably by inhibiting the Erk and Src signaling pathways. SHP2 has a particularly important role in maintaining liver cell homeostasis, and the increase and decrease of its expression will destroy the balance of liver cell signal transduction system, thereby affecting the occurrence and development of liver cancer. SHP2 is highly expressed in lung tissue of patients with pulmonary hypertension, and the expression of the SHP2 influences the pathogenesis process of hypoxic pulmonary hypertension by influencing the proliferation of pulmonary artery smooth muscle cells. Experiments show that SHP2 can dephosphorylate adhesion spot kinase and paxillin phosphorylation tyrosine of cytoskeletal molecules, further inhibit the formation of adhesion spots, and finally promote the movement of mouse fibroblasts. SHP2 is also involved in leukemia cell proliferation, and its overexpression affects leukemia cell malignant proliferation and apoptosis.
In conclusion, the research on the protein tyrosine phosphatase 2 target point has great significance for treating related diseases such as tumors and the like.
Disclosure of Invention
In view of the above, the present invention aims to provide 3 protein tyrosine phosphatase 2 receptor antagonists and applications thereof.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
the present invention provides compounds represented by structural formulas (I-III) and pharmaceutically acceptable salts thereof.
A compound represented by structural formula (I):
the common name is Echinocystic acid, the English name is Echinocystic acid, the CAS number is 510-30-5, and the molecular formula is C30H48O4And the molecular weight is 472.700.
A compound represented by structural formula (II):
is commonly named as plastic peruvian, English name is Prismerin, CAS number is 1258-84-0, and molecular formula is C30H40O4And the molecular weight is 464.636.
A compound represented by structural formula (III):
the common name is 3-Acetyl-11-keto- β -boswellic Acid, the English name is 3-Acetyl-11-keto- β -boswellic Acid, the CAS number is 67416-61-9, and the molecular formula is C32H48O5And the molecular weight is 512.721.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing medicaments for treating or preventing related diseases or symptoms caused by high expression or high activity of a protein tyrosine phosphatase 2 receptor.
The compound and the pharmaceutically acceptable salt thereof are used for preparing novel antitumor drugs.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing the medicine for treating allergic asthma.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing the medicament with the protective effect on atherosclerosis.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing the medicine for treating the pulmonary hypertension disease.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing the medicament for treating leukemia diseases.
A pharmaceutical composition comprises the above compound and its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.
The pharmaceutical composition further comprises a pharmaceutically acceptable excipient, diluent or carrier. Specifically, syrup, gum arabic, starch, etc. can be used. The pharmaceutical composition can be administered by intravenous, oral, sublingual, intramuscular or subcutaneous routes, or by the skin mucosa route.
The pharmaceutical composition is prepared in a liquid preparation or a solid preparation. Such as tablet, capsule and injection. The preparation can be prepared by a conventional pharmaceutical method.
A compound medicine comprises the compound and pharmaceutically acceptable salts thereof and medicines capable of being combined with the compound and the pharmaceutically acceptable salts thereof.
Compared with the prior art, the 3 protein tyrosine phosphatase 2 receptor antagonists and the application thereof have the following advantages:
IC of protein tyrosine phosphatase 2 receptor function test (SHP2 antagonistassay) of 3 compounds disclosed by the invention50On the micromolar scale, IC for Compounds 510-30-550IC of compound 1258-84-0 at 11.27. mu.M5018.96. mu.M; IC of 67416-61-9 of Compound5010.96. mu.M.
Drawings
FIG. 1 is a graph showing the inhibition rate of the compound 510-30-5 of the present invention on the protein tyrosine phosphatase 2 receptor in a functional assay;
FIG. 2 is a graph showing the inhibition rate of the compound 1258-84-0 of the present invention on the protein tyrosine phosphatase 2 receptor in a functional test;
FIG. 3 is a graph showing the inhibition rate of 67416-61-9 of the present invention on protein tyrosine phosphatase 2 receptor in functional experiments;
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention relates to compounds 510-30-5, 1258-84-0, 67416-61-9, all available from Doudster Biotechnology, Inc.
The present invention will be described in detail with reference to examples.
Examples
Experimental procedure
1. Preparing a reaction buffer:
50mM Tris-HCl，150mM NaCl，5mM DTT，1mM EDTA，0.003％BSA。
2. compound screening:
a. add 18. mu.l of reaction buffer to the dilution plate (249944, Nunc).
b. Transfer 2 μ l of the gradient dilution compound (see step 2.6.1.3) to each well of the dilution plate (see step a).
c. Shake on a shaker for 15 minutes.
d. Transfer 5 μ l of the gradient dilution compound (see step c) to the assay plate (784075, Greiner).
e. 4 XPTP SHP2(0.032ng/ul) was prepared with reaction buffer.
f. Add 5. mu.L of 4 XPTP SHP2 (see step e) to each well of the plate (see step d).
g. Plates were closed and incubated at room temperature for 10 minutes.
h. Preparation of 2 XDiFMUP (40. mu.M).
i. The reaction was initiated by adding 10. mu.l DiFMUP (see step h) to each well of the plate (see step f).
After j.2h, the fluorescence signal values were read at Enspire X (excitation wavelength: 360 nm; emission wavelength: 460 nm).
By the present example, 3 protein tyrosine phosphatase 2 receptor antagonists were found, the in vitro inhibitory activity of compound 510-30-5 was 11.27. mu.M, and the in vitro inhibitory activity of compound 1258-84-0 was 18.96. mu.M; the in vitro inhibitory activity of compound 67416-61-9 was 10.96. mu.M.
Claims (9)
1. A compound represented by structural formula (I-III):
2. use of the compound of claim 1 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of diseases or conditions associated with overexpression or overactivity of the protein tyrosine phosphatase 2 receptor.
3. The use of the compound of claim 1 and pharmaceutically acceptable salts thereof for the preparation of novel antitumor agents.
4. Use of a compound of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of allergic asthma.
5. Use of a compound of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament having protective effects against atherosclerosis.
6. The use of a compound of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of pulmonary hypertension, leukemia.
7. A pharmaceutical composition characterized by: comprising as an active ingredient a compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
8. A compound medicine is characterized in that: comprising the protein tyrosine phosphatase 2 receptor antagonist according to claim 1 in combination with a medicament capable of being administered in combination therewith.
9. Use of the pharmaceutical composition according to claim 7 for the preparation of a medicament for the treatment or prevention of a disease or disorder associated with overexpression or overactivity of the protein tyrosine phosphatase 2 receptor.
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| CN201911103378.3A CN110818769A (en) | 2019-11-13 | 2019-11-13 | Protein tyrosine phosphatase 2 receptor antagonist and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112062808A (en) * | 2020-09-29 | 2020-12-11 | 中南民族大学 | Compound extracted and separated from root of Caulophyllum robustum and application of compound in preparation of antidiabetic drugs |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112062808A (en) * | 2020-09-29 | 2020-12-11 | 中南民族大学 | Compound extracted and separated from root of Caulophyllum robustum and application of compound in preparation of antidiabetic drugs |
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Application publication date: 20200221 |