CN112142742B - CTCF transcription factor inhibitor and application thereof - Google Patents

CTCF transcription factor inhibitor and application thereof Download PDF

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CN112142742B
CN112142742B CN201910562893.1A CN201910562893A CN112142742B CN 112142742 B CN112142742 B CN 112142742B CN 201910562893 A CN201910562893 A CN 201910562893A CN 112142742 B CN112142742 B CN 112142742B
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transcription factor
compound
ctcf
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ctcf transcription
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柯子斌
马聪
张雅晶
陈颖祥
张玉琴
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Shenzhen Research Institute HKPU
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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a CTCF transcription factor inhibitor and application thereof. The CTCF transcription factor inhibitor provided by the invention comprises at least one of a compound I, a compound II, a compound III, a compound IV, a compound V and a compound VI as an active component; wherein R is1And R2Each independently selected from H, alkyl or alkoxy; r3Selected from H, halogen or alkyl; r4Selected from H, hydroxyl or alkoxy. The CTCF transcription factor inhibitor regulates and controls the transcription expression of the CTCF transcription factor by inhibiting the combination of the CTCF transcription factor and DNA, has good cancer cell toxicity activity, can effectively inhibit cancer cell metastasis, and has the potential of being applied to the preparation of anti-cancer drugs.
Figure DDA0002108766050000011

Description

CTCF transcription factor inhibitor and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a CTCF transcription factor inhibitor and application thereof.
Background
Liver cancer, known collectively as hepatocellular carcinoma (HCC), is the fifth of the global mortality in cancer, and HCC in china is the third highest mortality cancer following gastric and esophageal cancer. Due to the occult onset of HCC, high metastasis rate and lack of specific early tumor markers, many patients are already in the middle and late stages of cancer at the time of visit with mortality rates as high as 50%.
The traditional anti-liver cancer drugs lack targeting property, and can damage normal tissue cells to different degrees while killing cancer cells. With the development of tumor molecular biology and transformation medicine, the anti-tumor drug has been developed from the traditional cytotoxic drug to the non-cytotoxic drug, the non-cytotoxic drug mainly takes key regulation and control molecules and the like in the pathological process of tumor molecules as targets, and the anti-tumor drug has the characteristics of high selectivity and high therapeutic index, and has obvious clinical advantages. The Sorafenib (Sorafenib) is a multi-target kinase inhibitor drug for liver cancer and the like, inhibits the activity of receptor tyrosine kinases such as VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet-derived growth factor receptor) and the like by blocking a Ras/Raf/MEK/ERK signal conduction pathway, has high selectivity, and still has side effects such as fatigue, gastrointestinal tract reaction, skin rash, alopecia and the like. Other liver cancer therapeutic drugs such as Thiotepa (Thiotepa), Camptothecin (Camptothecin), Lenvatinib (Lenvatinib), Norcantharidin (Norcantharidin) and cucurbitacin b (cucurbitacin b) act on liver cancer cells through multiple targets, and have toxic side effects such as hypertension and hyperglycemia to various degrees. Therefore, the non-cytotoxic drug with definite curative effect and small toxic and side effect is provided for treating the liver cancer, and has important practical value.
Disclosure of Invention
The invention mainly aims to provide a CTCF transcription factor inhibitor, aiming at providing a non-cytotoxic drug with definite curative effect and small toxic and side effect for treating cancer.
Another object of the present invention is to provide the use of the above CTCF transcription factor inhibitor.
In order to achieve the purpose of the invention, the invention provides the following specific technical scheme:
the CTCF transcription factor inhibitor comprises at least one of a compound I, a compound II, a compound III, a compound IV, a compound V and a compound VI as an active component;
Figure BDA0002108766030000021
Figure BDA0002108766030000031
wherein R is1And R2Each independently selected from H, alkyl or alkoxy;
R3selected from H, halogen or alkyl;
R4selected from H, hydroxyl or alkoxy.
The CTCF transcription factor inhibitor provided by the invention has the active ingredients comprising the enumerated compounds, is targeted on the CTCF transcription factor, regulates and controls the transcription expression of the CTCF transcription factor by inhibiting the combination of the CTCF transcription factor and DNA, has good cancer cell toxicity activity, can effectively inhibit cancer cell metastasis, and has the potential of being applied to preparing anticancer drugs.
Correspondingly, the invention provides application of the CTCF transcription factor inhibitor in preparing anti-cancer drugs.
The CTCF transcription factor inhibitor provided by the invention has good cancer cell toxicity activity, can effectively inhibit cancer cell metastasis, and can be applied to preparation of anti-cancer drugs.
Drawings
FIG. 1 is a graph of the half inhibitory concentration (IC50) of each CTCF transcription factor inhibitor in test example 1;
FIG. 2 is a statistical result of cell migration numbers of CTCF transcription factor inhibitors of examples 1 to 6 in test example 2 after the experiment was finished;
FIG. 3 is a statistical result of cell migration numbers of CTCF transcription factor inhibitors of example 1 and example 8 in test example 2 after the experiment is finished;
FIG. 4 shows the result of staining of cells migrating in the blank group in test example 2;
FIG. 5 shows the results of staining of cells that migrated by the active ingredient of example 1 in test example 2;
FIG. 6 shows the results of staining of cells that migrated by the active ingredient of example 6 in test example 2;
FIG. 7 shows the results of staining of cells that migrated by the active ingredient of example 3 in test example 2;
FIG. 8 is a result of staining of cells that migrated by the active ingredient of example 5 in test example 2;
FIG. 9 shows the results of staining of cells that migrated by the active ingredient of example 4 in test example 2;
FIG. 10 is a result of staining of cells that migrated by the active ingredient of example 2 in test example 2;
FIG. 11 is a result of staining of cells migrated by the active ingredient of example 8 in test example 2;
FIG. 12 is the detection results of Western blotting experiments for CTCF transcription factor inhibitors of example 1 to example 6 in test example 3;
FIG. 13 is the detection results of Western blotting experiments for CTCF transcription factor inhibitors of examples 7, 1 and 9 in test example 3;
fig. 14 is a detection result of western blotting experiments for testing the CTCF transcription factor inhibitors of examples 8, 10, and 7 in example 3.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The CTCF transcription factor inhibitor comprises at least one of a compound I, a compound II, a compound III, a compound IV, a compound V and a compound VI as an active ingredient;
Figure BDA0002108766030000041
Figure BDA0002108766030000051
wherein R is1And R2Each independently selected from H, alkyl or alkoxy;
R3selected from H, halogen or alkyl;
R4selected from H, hydroxyl or alkoxy.
The CTCF transcription factor inhibitor provided by the embodiment of the invention has the active ingredients comprising the 6 compounds, is targeted on the CTCF transcription factor, regulates and controls the transcription expression of the CTCF transcription factor by inhibiting the combination of the CTCF transcription factor and DNA, has good cancer cell toxicity activity, can effectively inhibit cancer cell metastasis, and has the potential of being applied to the preparation of anti-cancer drugs.
The CTCF is also called CCCTC-binding factor, the binding site of the CTCF has 3 CCCTC repetitive sequences, the CTCF is a multifunctional transcription factor widely existing in eukaryote, can be combined with various genes and proteins through an 11 zinc finger structure of the CTCF, is widely involved in the expression regulation of the genes, and shows various biological properties. The applicant finds out in recent years[1]Since the decrease of CTCF reduces the mobility and invasiveness of cancer cells such as liver cancer cells, FOXM1 is one of important downstream effectors of CTCF in HCC, and ectopic expression of FOXM1 reverses the mobility and invasiveness of cancer cells, the cancer cells can be effectively inhibited from proliferating and metastasizing by reducing the expression of CTCF proteins in the cancer cells or inhibiting the binding of CTCF proteins to DNA. Through experimental detection, by adopting the enumerated compounds as active ingredients, the expression of FOXM1 protein of cancer cells such as liver cancer cell PLC5 cells can be effectively inhibited, the fact that the CTCF transcription factor inhibitor provided by the embodiment of the invention can effectively inhibit the transcription expression of CTCF transcription factors is shown, and recent researches show that FOXM1 is closely related to biological behaviors such as occurrence, invasion and metastasis of cancers, and the like, and reflect that the CTCF transcription factor inhibitor provided by the embodiment of the invention has potential value in preventing or treating cancers.
[1]Zhang,B.,Zhang,Y.,Zou,X.,Chan,A.W.,Zhang,R.,Lee,T.K.W.,...&Cheung,Y.S.(2017).The CCCTC-binding factor(CTCF)–forkhead box protein M1axis regulates tumour growth and metastasis in hepatocellular carcinoma.The Journal of pathology,243(4),418-430.
In the embodiment of the present invention, the alkyl refers to a kind of chain or cyclic organic group containing only two atoms of carbon and hydrogen, the general formula is represented as-R, and preferably, the number of carbon atoms is 1-20, and the unsaturation degree is 4 or less, including but not limited to methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, and the like. The alkoxy refers to a type of organic group containing oxygen and substituting hydrogen atoms of a compound parent nucleus by oxygen, has a general formula of-OR, is preferably alkoxy with the carbon atom number of 1-20 and the unsaturation degree of below 4, and comprises but is not limited to methoxy, ethoxy and the like. The halogen refers to VIIA group elements, including fluorine (F), chlorine (Cl), bromine (Br), iodine (I) and the like, preferably F, Cl and Br.
Preferably, R is1And said R2Each independently selected from H or alkoxy with carbon atom number of less than 6, R3Selected from H, F or alkyl with the carbon number of less than 6, R4Selected from H, hydroxyl or alkoxy with the carbon atom number of less than 6.
Preferably, the compound I comprises any one of the following compounds:
Figure BDA0002108766030000071
Figure BDA0002108766030000081
in some test examples, the compounds Ia to if show that the effective inhibition concentration of the expression of CTCF downstream protein FOXM1 of PLC5 cells is as low as 10 mu M, have good hepatoma cell cytotoxicity activity, can effectively inhibit hepatoma cell transfer, and can be effectively applied to the preparation of medicaments for preventing or treating hepatoma.
As a preferred embodiment, the active ingredients of the CTCF transcription factor inhibitor include: a compound I.
As another preferred embodiment, the active ingredients of the CTCF transcription factor inhibitor include: the compound I and at least one of the compound II, the compound III, the compound IV, the compound V and the compound VI. The combination of different types of compounds with hepatoma cytotoxic activity can reduce the dosage of the drug, improve the drug effect and avoid the toxic and side effects on normal cells caused by large dosage of single drug. In some embodiments, the active ingredients of the CTCF transcription factor inhibitor include: at least one of a compound Ia to a compound if, and at least one of a compound II, a compound III, a compound IV, a compound V and a compound VI.
As still another preferred embodiment, the active ingredients of the CTCF transcription factor inhibitor include: the compound I and the compound VI, and at least one of the compound II, the compound III, the compound IV and the compound V. In some embodiments, the active ingredients of the CTCF transcription factor inhibitor include: at least one of a compound Ia to a compound if, a compound VI, and at least one of a compound II, a compound III, a compound IV and a compound V.
As still another preferred embodiment, the active ingredients of the CTCF transcription factor inhibitor include: and (3) a compound VI. In some test cases, the compound shows that the compound has effective inhibition concentration of expression of CTCF downstream protein FOXM1 of PLC5 cells as low as 22.5 mu M, and has certain hepatotoxicity activity.
As other embodiments, the active ingredients of the CTCF transcription factor inhibitor include: a compound VI and at least one of a compound II, a compound III, a compound IV and a compound V. The compounds have certain hepatoma cell toxic activity, and the combination of various active compounds can effectively reduce the dosage of single medicine and improve the medicine effect.
In an embodiment of the present invention, the CTCF transcription factor inhibitor further includes at least one of a pharmaceutically acceptable adjuvant, an adjuvant, and a prodrug, and the active ingredient is uniformly mixed with the at least one of the pharmaceutically acceptable adjuvant, the adjuvant, and the prodrug in an effective dose. An effective dose is a therapeutically effective amount, and is a dose of the active ingredients of the embodiments of the present invention sufficient to show benefit or clinical significance to an individual. One skilled in the art will appreciate that the actual amount or dose administered and the time course of administration will depend on the nature and severity of the disease being treated, the age and general condition of the subject being treated, and the mode of administration, among other factors. The CTCF transcription factor inhibitor is administered to a subject via oral administration, intravenous injection, intravenous infusion, intraperitoneal injection, hepatic arterial embolization chemotherapy, intramuscular injection, and/or subcutaneous injection.
The pharmaceutically acceptable excipients refer to any excipients known to those skilled in the art to be suitable for a particular mode of administration, for example, in particular embodiments, the pharmaceutically acceptable excipients may include one or more pharmaceutically acceptable carriers, solvents, excipients, buffers, lubricants, compatible with the active ingredients of the embodiments of the invention. The adjuvant should be non-toxic, non-interfering with or not detrimental to the efficacy of the active ingredients of the embodiments of the present invention, and may be selected for flexibility in the particular dosage form of the CTCF transcription factor inhibitor described in the above embodiments. Such carriers include, but are not limited to, sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, celluloses and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, and the like. Such excipients include, but are not limited to, cocoa butter, suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as propylene glycol, esters such as ethyl oleate and ethyl dodecanoate, and agar, and the like. The buffer includes, but is not limited to, at least one of magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, phosphate buffer solution, and the like. Such lubricants include, but are not limited to, sodium lauryl sulfate and magnesium stearate, among others. Further, coloring agents, releasing agents, coating agents, sweeteners, flavoring agents, aromatics, preservatives and antioxidants may also be used as the adjuvants, according to the judgment of the person skilled in the art.
Preferably, the dosage form of the CTCF transcription factor inhibitor includes at least one of a solution, a pill, a tablet, a capsule, a powder, a paste, an aerosol, and a patch.
Correspondingly, the invention provides application of the CTCF transcription factor inhibitor in preparing anti-cancer drugs.
The CTCF transcription factor inhibitor provided by the embodiment of the invention has good cancer cell toxicity activity, can effectively inhibit cancer cell metastasis, and can be applied to preparation of a medicament for preventing or treating cancer.
In the present embodiment, the anticancer drug refers to a drug for preventing or treating cancer including, but not limited to, liver cancer, lung cancer, breast cancer, intestinal cancer, stomach cancer, prostate cancer, pancreatic cancer, ovarian cancer, cervical cancer, and the like. Preferably, the anticancer drug is a drug for preventing or treating liver cancer. In some test examples, the CTCF transcription factor inhibitor shows that the effective inhibition concentration of the CTCF downstream protein FOXM1 of the PLC5 cell is as low as 10 mu M, has good hepatoma cell cytotoxicity activity, can effectively inhibit hepatoma cell transfer, and can be effectively applied to preparation of medicaments for preventing or treating hepatoma.
In order that the above-described implementation details and operation of the present invention will be clearly understood by those skilled in the art, and the advanced performance of a CTCF transcription factor inhibitor and its application in the embodiments of the present invention will be apparent, the implementation of the present invention will be illustrated by the following examples.
Examples 1-11 provide CTCF transcription factor inhibitors comprising an effective amount of an active ingredient, and an adjuvant; wherein, the active ingredients are shown in table 1:
TABLE 1
Figure BDA0002108766030000101
Figure BDA0002108766030000111
Figure BDA0002108766030000121
Test example 1
In this test example, hepatoma cell PLC5 cells were selected, and the half inhibitory concentration (IC50,%) of the CTCF transcription factor inhibitor provided in examples 1 to 11 on PLC5 cells was tested, and the test results are shown in fig. 1, which shows that the CTCF transcription factor inhibitor provided in examples 1 to 7 has a high inhibitory effect on the growth of PLC5 cells.
Test example 2
In this test example, hepatoma cell PLC5 cells were selected, and cell migration experiments were performed using the CTCF transcription factor inhibitors provided in examples 1 to 6 and 8, using a Transwell chamber having a polycarbonate membrane with a pore size of 8 μm.
The Transwell chamber is put into a culture plate, the chamber is called an upper chamber, the culture plate is called a lower chamber, the culture solution in the upper chamber and the culture solution in the lower chamber are separated by a polycarbonate membrane, and due to the permeability of the polycarbonate membrane, the components in the culture solution in the lower layer can affect the cells in the upper chamber, so that the influence of the components in the culture solution in the lower layer on the growth, movement and the like of the cells, such as the research of various aspects of cell migration, cell invasion and the like, is researched.
The CTCF transcription factor inhibitors provided in examples 1-6 and 8 were mixed with PLC5 cells and incubated for 24 hours, respectively, and then the cells were digested, washed 1 time with PBS, suspended in serum-free medium, counted, and adjusted to a concentration of 4X 105and/mL. Adding 500 μ L of culture medium containing 10% serum into the lower chamber of the Transwell (i.e., the bottom of the 24-well plate), adding 100 μ L of cell suspension into the upper chamber, and then, continuously culturing in an incubator for 16 h; then, the culture solution in the lower chamber is soaked in 70% methanol solution, fixed for 20min, and the cells are stained with 0.5% crystal violet, which is a basic dye and can be combined with DNA in cell nucleus, so that the cells are stained into bluish purple; and then, performing microscopic examination, counting the stained cells under a microscope, and if the counting value is high, the group of cells has strong migration capacity.
Fig. 2 is a statistical result of cell migration numbers of the CTCF transcription factor inhibitors of examples 1-6 after the experiment was finished, and the tested concentration is 10 μ M, and fig. 2 shows that the CTCF transcription factor inhibitors of examples 1-6 can significantly inhibit liver cancer cell migration compared to the blank group.
FIG. 3 is a statistical result of cell migration numbers of CTCF transcription factor inhibitors of example 1 and example 8 after the end of the experiment, the tested concentration of the compound Ia of example 1 was 10 μ M, and the tested concentration of the compound V of example 8 was 1600 μ M, and FIG. 3 shows that the compound Ia of example 1 is superior to the compound V of example 8 in inhibiting the migration of liver cancer cells.
FIG. 4 is a result of staining of cells migrated in the blank group, FIG. 5 is a result of staining of cells migrated by the active ingredient of example 1, FIG. 6 is a result of staining of cells migrated by the active ingredient of example 6, FIG. 7 is a result of staining of cells migrated by the active ingredient of example 3, FIG. 8 is a result of staining of cells migrated by the active ingredient of example 5, FIG. 9 is a result of staining of cells migrated by the active ingredient of example 4, FIG. 10 is a result of staining of cells migrated by the active ingredient of example 2, and FIG. 11 is a result of staining of cells migrated by the active ingredient of example 8. As shown in fig. 4 to 11, the CTCF transcription factor inhibitors provided by the embodiments of the present invention have the ability to effectively inhibit cell migration relative to the blank group.
Test example 3
In the test example, a Western Blotting experiment is performed, a liver cancer cell PLC5 cell is selected, the test analyzes the influence of the CTCF transcription factor inhibitors provided in examples 1 to 11 on the protein expression of the PLC5 cell under different concentrations, DMSO is added to a blank group to replace samples added to other test groups, and Actin is internal reference protein. As shown in the results of the tests in fig. 12 to fig. 14, FOXM1, which is a CTCF downstream expression protein, was inhibited to various degrees in each test group to which the CTCF transcription factor inhibitors of this example were added.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (3)

1. The CTCF transcription factor inhibitor is characterized in that the active ingredient of the CTCF transcription factor inhibitor is a compound I, and the compound I is any one of the following compounds:
Figure FDA0003316764450000011
Figure FDA0003316764450000021
2. the CTCF transcription factor inhibitor according to claim 1, further comprising at least one of pharmaceutically acceptable adjuvants and adjuvants.
3. Use of the CTCF transcription factor inhibitor of any one of claims 1 to 2 for the preparation of an anti-cancer medicament.
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