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Application of phenylacrylic compounds to preparation of Shp2-specific inhibitors and pharmaceutical application thereof

A technology of phenylacrylic acid compounds, which is applied in the field of preparing Shp2 specific inhibitors of phenylacrylic acid compounds, and can solve problems such as few and difficult development

Active Publication Date: 2018-09-28
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since PTPs all have highly conserved and positively charged PTP domains, and more than 60% of the sequences in Shp1 and Shp2 are identical, in addition, cell permeability, bioavailability and selectivity must be overcome, and the specificity of Shp2 must be developed. However, it is very difficult to find a specific inhibitor of Shp2. At present, no specific inhibitor of Shp2 has entered clinical trials, and there are not many Shp2 inhibitors that have been found, mainly including chemically synthesized compounds SHP099, NSC-87877, PHPS1 and natural products. Cryptotanshinone, Allosterase, Fumosinone (Fumos), etc.

Method used

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  • Application of phenylacrylic compounds to preparation of Shp2-specific inhibitors and pharmaceutical application thereof
  • Application of phenylacrylic compounds to preparation of Shp2-specific inhibitors and pharmaceutical application thereof
  • Application of phenylacrylic compounds to preparation of Shp2-specific inhibitors and pharmaceutical application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Example 1: Establishment of a model for high-throughput screening of PTP-Shp2 protein inhibitors in vitro

[0040] 1) Prokaryotic expression and purification of PTP-Shp2, Shp1, VHR, HePTP proteins

[0041] After pGEX4T-1-PTP-Shp2, pGEX4T-1-Shp1, pGEX4T-1-VHR, pGEX4T-1-HePTP plasmids (provided by the laboratory of Professor Feng Gensheng, University of California, San Diego) transformed into BL21Star (DE3) competent cells, 37 Cultivate overnight in an incubator at ℃, pick a single colony and shake it in LB medium to obtain a large amount of bacterial liquid. A large amount of bacterial liquid expressing PTP-Shp2 protein was at 20°C, and a large amount of bacterial liquid expressing Shp1, VHR, HePTP protein was induced overnight at 0.1mMIPTG160r / min at 25°C, and the bacterial cells were collected by centrifugation, resuspended and ultrasonically disrupted And purification, and then use SDS-PAGE electrophoresis to verify the purification effect. PTP-Shp2, Shp1, VHR, and ...

Embodiment 2

[0056] Example 2: Effect of H320 (isoferulic acid) on the activation of Shp2-dependent Erk induced by EGF

[0057]Previous studies have shown that Shp2 can participate in the regulation of the Ras / Erk signaling pathway. In cells, the growth factor EGF can cause the cascade reaction of the Erk pathway in a Shp2-dependent manner, thereby causing an increase in the phosphorylation level of Erk. Therefore, we tested at the cellular level whether the PTP-Shp2 inhibitor H320 (isoferulic acid) obtained by our high-throughput screening could affect EGF-induced Erk phosphorylation by inhibiting the activity of Shp2. 293T cells after overnight serum starvation were treated with different concentrations of H320 (isoferulic acid) (0 μM, 10 μM, 20 μM, 30 μM) for 24 h, stimulated with EGF (2 ng / ml) for 10 min, and then added a certain volume of RIPA lysate, Proteins were harvested and Westernized. from Figure 5 It can be seen that, under no drug treatment, the level of p-Erk was signific...

Embodiment 3

[0058] Example 3: Effect of H335 (cinnamic acid) on EGF-induced activation of Shp2-dependent Erk

[0059] Previous studies have found that Shp2 is necessary for the maintenance of related cellular functions in breast cancer MDA-MB-468 cells. We detected the effect of H335 (cinnamic acid) on the Ras / Erk signaling pathway regulated by Shp2 in MDA-MB-468 cells. MDA-MB-468 cells were starved for 16 h, treated with different concentrations of H335 (cinnamic acid) (0 μM, 10 μM, 20 μM) for 3 h, induced with 2 ng / ml EGF for 10 min, and the expression levels of p-Erk, Erk, Shp2, and GAPDH were detected by Western analysis. Image 6 It shows that adding different concentrations of H335 (cinnamic acid) to treat MDA-MB-468 cells can significantly reduce the expression level of p-Erk induced by EGF. Next, we also tested whether the inhibitory effect of H335 (cinnamic acid) on Shp2 is time-sustained, and found that p-Erk was not up-regulated at different times of EGF induction, indicating ...

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Abstract

The invention discloses the application of phenylacrylic compounds to the preparation of Shp2-specific inhibitors and pharmaceutical application thereof. The invention finds that two phenylacrylic compounds, namely isoferulic acid and cinnamic acid, have a specific inhibitory effect on Shp2 and the isoferulic acid and the cinnamic acid can be prepared into the Shp2-specific inhibitors. The invention further verifies that both the isoferulic acid and the cinnamic acid can inhibit EGF-induced phosphorylation of Erk by inhibiting the activity of the Shp2 in the cellular level, the cinnamic acid can also inhibit EGF-induced migration of MDA-MB-468 cells, and the isoferulic acid and the cinnamic acid are expected to be developed into medicines for preventing or treating of Shp2-related diseasesand are of a great significance on the development of the medicines targeting the Shp2.

Description

technical field [0001] The invention relates to the use of phenylacrylic acid compound in preparing Shp2 specific inhibitor and its pharmaceutical use. Background technique [0002] Shp2 is an intracellular non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. It is a member of the PTPs family. It is widely expressed in embryos and various adult tissues. It is an evolutionarily conserved protein composed of two Consists of a tandem N-terminal SH2 domain (N-SH2, C-SH2), a PTP domain with tyrosine phosphatase activity, and a C-terminus rich in proline groups and tyrosine phosphorylation sites . The activity regulation of Shp2 is mainly related to the N-SH2 domain. In the basal state, the N-SH2 domain of Shp2 can interact with the PTP domain, and the PTP domain is not exposed through intramolecular mutual inhibition. It is maintained in a self-inhibited state without phosphatase activity. When a ligand containing phosphorylated tyrosine residues binds to the N...

Claims

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Application Information

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IPC IPC(8): A61K31/192A61P35/00A61P35/02
Inventor 吕忠显王贵洲罗强朱健波
Owner XIAMEN UNIV
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