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A small molecule inhibitor of stat3 signaling pathway and its application in the preparation of antitumor drugs

An anti-tumor drug and inhibitor technology, used in anti-tumor drugs, drug combinations, nitrile/isonitrile active ingredients, etc., can solve the problems of poor bioavailability and difficult medicinal use, and achieve inhibiting tumor cell proliferation and inducing tumors. effect of apoptosis

Inactive Publication Date: 2016-08-03
江苏集萃医学免疫技术研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although many compounds have been reported to inhibit STAT3 signaling, most of them play a major role in targets other than STAT3 or are easily metabolized polypeptide compounds with poor bioavailability and difficult to be used medicinally

Method used

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  • A small molecule inhibitor of stat3 signaling pathway and its application in the preparation of antitumor drugs
  • A small molecule inhibitor of stat3 signaling pathway and its application in the preparation of antitumor drugs
  • A small molecule inhibitor of stat3 signaling pathway and its application in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: 2-[2-(3-Chloro-4-fluorobenzene) hydrazino]-3-(4-chlorophenyl)-3-oxopropionitrile

[0039]

[0040] The above compounds are used as small molecule inhibitors of STAT3 signaling pathway. This compound is commercially known as KM55 and is commercially available, for example, from Maybridge Chemicals, UK.

Embodiment 2

[0041] Example 2: Inhibition of STAT3 Phosphorylation by Small Molecule Inhibitors of STAT3 Signaling Pathway

[0042] The multiple myeloma cell lines U266, RPMI-8226 and OPM2 cells were treated with different concentrations of STAT3 signaling pathway small molecule inhibitors for 24 hours, then lysed with SDS protein lysate containing sodium orthovanadium, and 30 μg of protein was taken for gel electrophoresis to detect The expression of p-STAT3 and STAT3, and the phosphorylation levels of STAT3 upstream and downstream proteins JAK2, Src, STAT3, etc. were detected, and GAPDH or actin was used as an internal reference.

[0043] figure 1 It is the inhibitory effect of small molecule inhibitors of STAT3 signaling pathway on STAT3 phosphorylation, see figure 1A, it can be seen that STAT3 phosphorylation is inhibited by small molecule inhibitors of STAT3 signaling pathway in three kinds of cells; figure 2 and image 3 Respectively, the small molecule inhibitors of the STAT3 si...

Embodiment 3

[0044] Example 3: Inhibitory effect of small molecule inhibitors of STAT3 signaling pathway on IL-6-induced STAT3 activation

[0045] Multiple myeloma cells (RPMI-8226, OPM2) were cultured with low serum (0.5%) overnight, treated with drugs (KM55 or DMSO) for 2 hours, and then acted with IL-6 for 20 minutes. The cells were collected and stained with SDS containing sodium orthovanadide. The total protein was extracted from the protein lysate, and the expression of phosphorylated STAT3 (p-STAT3) and total STAT3 was detected by Western blot, and GAPDH was used as an internal reference.

[0046] Figure 4 It is a graph showing the inhibitory effect of small molecule inhibitors of STAT3 signaling pathway on the STAT3 induction of IL-6. It was found that small molecule inhibitors of STAT3 signaling pathway can significantly inhibit the activation of STAT3 induced by IL-6.

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Abstract

The invention discloses an STAT (Signal Transducer And Activator Of Transcription)3 signal channel small-molecule inhibitor and application thereof. The inhibitor is expressed in a chemical structural formula which is shown in the specification, wherein R1 is halogenated aryl, R2 is halogenated aryl, R3 is oxygen or sulphur. The inhibitor has functions of effectively inhibiting the multiplication of various tumor cells and inducing the apoptosis of the various tumor cells. The newly developed STAT3 signal channel small-molecule inhibitor not only has a remarkable inhibition effect on the phosphorylation of the STAT3, but also has the remarkable inhibition effect on the IL-6-induced STAT3 activation and the activation of the STAT3 upstream signal CrC and Jak2, and therefore, the multiplication of the various tumor cells can be inhibited and the apoptosis of tumor cells can be induced. Besides, the STAT3 signal channel small-molecule inhibitor has an in-vitro and vivo treatment effect on various tumors of acute and chronic leukemia, multiple myeloma, lymphoma, lung cancer, prostate cancer, cervical cancer and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to STAT3 inhibitors, in particular to a small molecule inhibitor of STAT3 signaling pathway and application thereof. Background technique [0002] Cancer is still one of the main causes of death in humans. Clinicians and scientists are working on the improvement of tumor treatment methods, such as improving surgical techniques, refining radiotherapy, and developing new chemical agents. Although these efforts are beneficial to the development of cancer treatment, the current tumor There is still a lot of room for development in the treatment, and discovering new anti-tumor drugs with low toxicity, high efficiency and high specificity is an important research direction for life scientists. [0003] Signal Transducer and Activator of Transcription-3 (STAT3 for short) is a related protein that can be activated by different cytokine receptors, and acts as a carrier in the process of cyto...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/275A61P35/00A61P35/02
Inventor 毛新良杜晓林
Owner 江苏集萃医学免疫技术研究所有限公司
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