CN112933235A - Application of compound targeting SOAT1 protein in preparation of drugs for preventing and/or treating liver cancer - Google Patents
Application of compound targeting SOAT1 protein in preparation of drugs for preventing and/or treating liver cancer Download PDFInfo
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- CN112933235A CN112933235A CN202110371783.4A CN202110371783A CN112933235A CN 112933235 A CN112933235 A CN 112933235A CN 202110371783 A CN202110371783 A CN 202110371783A CN 112933235 A CN112933235 A CN 112933235A
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Abstract
The invention discloses a group of drugs or compounds targeting SOAT1 protein, which are Nilotinib (AMN-107), Ramipril (Altag), ABT-737 and Evactrapib (LY 2484595). Experiments show that the medicine and the positive control medicine Avasimibe can inhibit the conversion of cholesterol to cholesterol ester by combining with SOAT1, and increase the intracellular cholesterol level. Further, cell proliferation experiments of the medicines on three cells, namely a liver cancer cell line HepG2, PLC and 97L show that the medicines can obviously inhibit the growth of liver cancer cells and obtain an IC50 value superior to that of a positive medicine, namely Avasimibe. The invention provides a new liver cancer treatment targeted drug from the angle that targeted SOAT1 protein influences cholesterol steady state, and provides a new direction for clinical treatment of liver cancer.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a group of micromolecular medicines of a targeted cholesterol steady-state target SOAT1 protein, which has a prospect of treating liver cancer.
Background
Cholesterol is an essential lipid component for maintaining cell homeostasis. It is a major component of cell membranes, in addition to being a precursor for the synthesis of bile acids, steroid hormones and vitamin D, is enriched in lipid rafts and plays an important role in cell signaling. Researches find that cholesterol metabolism reprogramming exists in the process of generating and developing tumor cells, the intracellular cholesterol level is obviously increased, and metabolites of the intracellular cholesterol level are abnormally accumulated. In the early stage, the study on the proteome and the phosphoproteome of 101 cases of early hepatocellular carcinoma and matched paracancerous tissue samples discovers that the currently clinically considered early hepatocellular carcinoma patients can be divided into three proteome subtypes, while the patients with different subtypes have different prognosis characteristics (S-I, S-II and S-III) and need different treatment schemes after operation. In particular, proteomic studies of patients with third-class hepatocellular carcinoma have found that the cholesterol metabolic pathway is reprogrammed, and the high expression of a candidate drug target cholesterol esterase (SOAT1) has the worst prognosis risk, which indicates that the SOAT1 protein plays an important role in regulating cholesterol homeostasis and in the development of liver cancer.
In recent years, development of anti-tumor drugs targeting the SOAT1 protein is also ongoing, for example, Avasimibe is firstly used as a lipid regulating drug for treating atherosclerosis, and recently, the anti-tumor drugs are also found to have a treatment effect on pancreatic cancer, liver cancer and the like; in addition, small molecules such as Nevanimibe, CL-976 and the like are reported to have a eutectic three-dimensional structure with SOAT1 protein and have the effect of inhibiting the activity of the protein. However, the studies are still in preclinical research, so that drug screening is performed around a target SOAT1 affecting cholesterol homeostasis, and a new small molecule with an anti-tumor effect is found by combining tumor cells and cholesterol homeostasis analysis and verification, so that a new direction is provided for targeted therapy of liver cancer.
Disclosure of Invention
The invention aims to provide a new application of a group of drugs/compounds targeting SOAT1 protein.
The new application of the drug/compound targeting the SOAT1 protein provided by the invention is the application of the drug/compound in preparing a drug for preventing and/or treating liver cancer.
The new application of the drug/compound targeting the SOAT1 protein provided by the invention is the application of the drug/compound in the preparation of liver cancer cell proliferation inhibitors.
The drug/compound targeting the SOAT1 protein is combined with the SOAT1 protein and inhibits the growth of hepatoma cells.
The invention also includes the use of drugs/compounds targeting the SOAT1 protein in:
1) preventing and/or treating liver cancer;
2) inhibiting proliferation of hepatocarcinoma cell.
The liver cancer cell can be HepG2, PLC/PRF/5(PLC) and MHCC97L (97L).
The drug/compound targeting the SOAT1 protein is specifically selected from at least one of the following: nilotinib (AMN-107), Ramipril (Alpace), ABT-737 and Evactrapib (LY 2484595).
Among them, Nilotinib (AMN-107), Cas No.: 641571-10-0, the structural formula is shown as follows:
ramipril (altace), Cas No.: 87333-19-5, the structural formula is shown as follows:
ABT-737, Cas No.: 852808-04-9, the structural formula is shown as follows:
evacetrrapib (LY2484595), CAS No.1186486-62-3, having the structural formula:
the Nilotinib (AMN-107) has obvious inhibition effect on three liver cancer cells HepG2, PLC and 97L, IC50448.5nM, 15.7. mu.M and 2.44. mu.M, respectively.
The Ramipril (Altace) has obvious inhibition effect on three liver cancer cells HepG2, PLC and 97L, and IC5096.8nM,25.1nM and 6.0. mu.M, respectively.
The ABT-737 has obvious inhibiting effect on three kinds of liver cancer cells HepG2, PLC and 97L, and IC50184.0nM, 3.3. mu.M and 2.1. mu.M, respectively.
The Evactrapib (LY2484595) has obvious inhibition effect on three liver cancer cells HepG2, PLC and 97L, and IC509.2. mu.M, 5.6. mu.M and 2.0. mu.M, respectively.
The invention also provides a product, which is characterized in that: the active ingredient of the product is at least one of Nilotinib (AMN-107), Ramipril (Alpace), ABT-737 and Evactrapib (LY 2484595).
The product has at least one of the following effects:
1) for preventing and/or treating liver cancer;
2) inhibiting proliferation of hepatocarcinoma cell.
Illustratively, the product may be a medicament or pharmaceutical formulation.
The product may contain, in addition to the active ingredient, a suitable carrier or excipient. The carrier material herein includes, but is not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, carboxymethyl cellulose, etc.). Among these, water-soluble carrier materials are preferred. The materials can be prepared into various dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, freeze-dried powder injections and the like. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. In order to prepare the dosage form for unit administration into a pill, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. In order to prepare the unit dosage form into suppositories, various carriers known in the art can be widely used. As examples of the carrier, there may be mentioned, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. In order to prepare the unit dosage form into preparations for injection, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, etc., can be used. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired. The preparation can be used for injection administration, including subcutaneous injection, intravenous injection, intramuscular injection, intracavity injection and the like; for luminal administration, such as rectally and vaginally; administration to the respiratory tract, e.g., nasally; administration to the mucosa.
The invention also provides a method for preventing and/or treating liver cancer, which comprises the following steps: administering the drug/compound targeting the SOAT1 protein to a recipient animal or human for the prevention and/or treatment of liver cancer.
In the present invention, the animal may be a mammal.
The four drugs/compounds described in this invention can bind to the SOAT1 protein and affect intracellular cholesterol homeostasis.
The four medicines or compounds can obviously inhibit the growth of hepatoma carcinoma cells, compared with Avasimibe, Nilotinib (AMN-107), Ramipril (Altance) and ABT-737 have better effects than positive medicine Avasimibe, and the Evactrapib has basically the same effect as the positive medicine. Cholesterol homeostasis experiments also showed that these drugs, by binding to SOAT1, inhibited the conversion of cholesterol to cholesterol esters, elevated intracellular cholesterol levels; and can achieve the effect of increasing intracellular cholesterol at lower drug concentration. The invention provides a new liver cancer treatment targeted drug from the angle that targeted SOAT1 protein influences cholesterol steady state, and provides a new direction for clinical treatment of liver cancer.
Drawings
Figure 1 is a high throughput screen based on the SOAT1 target protein. Several drugs or compounds are shown to bind to the binding pocket and potential binding site of the SOAT1 protein.
FIG. 2 is the liver cancer cell viability assay by small molecule screening. The graph shows the cell viability measured with CCK-8 after 24h and Avasimibe as a positive control given two concentrations of 2. mu.M and 20. mu.M, respectively, for the four drugs in HepG2 cells.
FIG. 3 shows the activity IC of Nilotinib on three liver cancer cells HepG2, PLC and 97L50And (4) measuring.
FIG. 4 shows the activity IC of Ramipril on three liver cancer cells HepG2, PLC and 97L50And (4) measuring.
FIG. 5 shows that ABT-737 has three kinds of liver cancer cell HepG2, PLC and 97L cell activity IC50And (4) measuring.
FIG. 6 shows that Evacetrapib has activity IC on three liver cancer cells HepG2, PLC and 97L50And (4) measuring.
FIG. 7 is a drug versus cell cholesterol homeostasis assay. The figure is 2 times IC of the four medicaments respectively50At the dosing concentration, intracellular cholesterol staining was performed with filibin, and Avasimibe was the positive control.
Fig. 8 is a comparison of the activity of the four drugs in HepG2 cells with the positive control Avasimibe.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Nilotinib (AMN-107) used in the examples below was purchased from Selleck, catalog No. S1033; ramipril (Altace) from Selleck, catalog number S1793, ABT-737 from Selleck, catalog number S1002; evacet rapib (LY2484595) from Selleck, catalog number S2825; avasimibe was purchased from Selleck, catalog number S2187.
The liver cancer cells HepG2 used in the examples described below were purchased from ATCC, product number ATCC HB-8065; PLC from ATCC, product number ATCC CRL-8024; 97L was purchased from ATCC (agency of Wuhan Protech, Bio Inc.), product number CL-0497.
Example 1: high throughput screening based on SOAT1 target proteins
The three-dimensional crystal structure of the SOAT1 protein described in this example is derived from RCSB PDB database, two models of SOAT1 protein PDB code 6L47 and 6VUM were selected for high-throughput ligand screening, and the small molecule database is derived from FDA and select compounds library. The docking software comprises four docking methods (two docking methods of glide fraction SP and XP) of three software including AutoDock 4.2, sybyl 2.0 and glide to carry out primary screening on all the compounds to be screened.
Specifically, before molecular docking, docking pockets were first defined, and the experiment mainly used the hydrophobic pocket of the SOAT1 protein, the C channel, the T channel, and the NTD-terminal binding pocket as the main active docking pockets. For AutoDock 4.2 and sybyl 2.0, a lattice was created around the four active pockets described above (set at a distance of about 15 angstroms in size) and added to SOAT1 and the compound to be docked by adding polar hydrogen and a gastiger-Huckel partial charge. The conformational sampling of SOAT1 and the compound were set to be rigid and flexible, respectively. Genetic algorithms and empirical free energy functions are used to generate and take into account docking gestures, respectively. For glide SP and XP patterns, protein and compound pre-treatments were as above, docking results were refined by post-docking energy minimization and docking results were evaluated by scoring functional glideScore. After all these docking steps are completed, the docking results will be merged, with the top 20% of compounds ranked in all docking tools and with a degree of aggregation greater than 80% being considered as potential active compounds. Then, high-precision docking is further carried out through glidedocking, and the result is visually displayed and plotted in pymol software. The docking results of Nilottinib (AMN-107), Ramipril (Alpace), ABT-737, Evactrapib (LY2484595) and the positive control Avasimibe are shown in FIG. 1, and the docking scores of all the four drugs are smaller than those of the positive control, and show good binding with SOAT 1.
Example 2: screening of small molecules for determination of liver cancer cell viability
To explore the activity of the four screened compounds on hepatoma cells, we continued cell viability assays.
The cells used in this example were HepG2 cells, and the test drugs were Nilotinib (AMN-107), Ramipril (Alrace), ABT-737 and Evactrapib (LY2484595), with an additional blank control and a positive control (Avasimibe). Specifically, the method comprises the following steps:
1) 8000/well HepG2 cells were seeded in 96-well plates in DMEM medium containing 10% fetal bovine serum at 37 deg.C with 5% CO2Culturing for 12-24 h in a culture environment, and adding the diluted medicine when the cells grow to about 70%.
2) The four drugs and positive control were diluted to 2. mu.M and 20. mu.M in cell culture medium, and DMSO was used as a blank control.
3) Old medium was removed and diluted drug (formulated in cell culture medium) was added to the 96-well plates containing cells and labeled, repeating in triplicate for each concentration.
4)37℃，5％CO2And continuously culturing for 24-48h in the culture environment, adding 10 mu L/hole of CCK-8 reagent, and continuously culturing for 1 h.
5) The absorbance of the incubated samples was measured at 450nM using a microplate reader, the data collected and plotted for analysis in a graphipad prism 9.0.
As shown in FIG. 2, Nilotinib (AMN-107), Ramipril (Alpace), ABT-737 and Evactrapib (LY2484595) can significantly inhibit the growth of HepG2 cells at both 2. mu.M and 20. mu.M concentrations.
Example 3: four screened drugs/compounds for three hepatoma cells IC50Measurement of
To further explore the activity of four compounds on hepatoma cells, we performed cellular IC50And (4) measuring. Specifically, the method comprises the following steps:
1) 8000/well HepG2, PLC and 97L liver cancer cells are respectively planted in a 96-well plate, and are cultured for 12-24 hours in a DMEM culture medium containing 10% fetal calf serum at 37 ℃ in a 5% CO2 culture environment, and diluted medicines are added when the cells grow to about 70%.
2) The four drugs were diluted from 10mM to 100. mu.M, 50. mu.M, 25. mu.M, 10. mu.M, 5. mu.M, 1. mu.M, 100nM, 10nM, 1nM, and 0 ten concentration points, respectively.
3) The old medium was removed and the diluted drug (media matched) was added to a 96-well plate containing HepG2, PLC and 97L hepatoma cells and labeled, each concentration being repeated in triplicate.
4)37℃，5％CO2And continuously culturing for 24-48h in the culture environment, adding 10 mu L/hole of CCK-8 reagent, and continuously culturing for 1 h.
5) The absorbance of the incubated samples was measured at 450nM using a microplate reader, the data collected and plotted for analysis in a graphipad prism 9.0.
IC measurements of several drugs in three cells50As shown in FIGS. 3 to 6, the cell growth inhibitory effect was excellent at a low drug concentration.
Example 4: drug-on-cell cholesterol homeostasis assay
This example is mainly used to investigate the effect of four compounds on intracellular Cholesterol of hepatoma cells, and the method used is the phenanthroline III intracellular Cholesterol staining (Cholesterol cell-based detection assay kit, No. 10009779). The principle is that Philippinin III can bind to cholesterol on the membrane and emit blue light to develop color. While SOAT1 is an important intracellular cholesterol homeostasis regulatory protein that can convert cholesterol into cholesteryl esters, when SOAT1 is inhibited, the conversion of intracellular cholesterol into cholesteryl esters is limited and intracellular cholesterol will rise. This experiment explores the effect of drugs on cellular cholesterol. Specifically, the method comprises the following steps:
1) 8000/well HepG2 was seeded in 96 well plates in DMEM medium containing 10% fetal calf serum at 37 deg.C with 5% CO2Culturing for 12-24 h in a culture environment, and adding the diluted medicine when the cells grow to about 70%.
2) The above Nilotinib (AMN-107), Ramipril (Alpace), ABT-737, Evactrapib (LY2484595) and Avasimibe were diluted to 1. mu.M, 200nM, 400nM, 20. mu.M and 10. mu.M, respectively (IC of each drug versus HepG 2)50Two times the dose).
3) Old media was removed and diluted drug (media-matched) was added to the cell-containing 96-well plates and labeled, each concentration being repeated in triplicate.
4)37℃，5％CO2And continuously culturing for 12-24 h in the culture environment (the cells grow to about 70-80 percent and the best observation effect is obtained), and then dyeing according to the instruction of the cholesterol filipin III alcohol dyeing kit.
5) After removing the culture medium from the cultured cells, the cells were washed with PBS 3 times 50. mu.L of PBS buffer each time in a shaker at 100 rpm for 5 minutes at room temperature.
6) The washed HepG2 cells were fixed for 15 minutes at room temperature in a cell fixing solution (Item No. 10009866). Then, the mixture was washed 3 times with 50. mu.L of PBS buffer each time on a shaker at 100 rpm for 5 minutes.
7) The Philippinin III stock solutions were mixed as 1: 100 dilutions (Item No.10009868) were added to each well 100. mu.L of diluted solution and incubated for 30-60min in the absence of light (care was taken to avoid light as much as possible for this step). Then, the mixture was washed 3 times with 50. mu.L of PBS buffer each time on a shaker at 100 rpm for 5 minutes.
8) And (3) observing the washed sample under a 20-time microscope, wherein the excitation wavelength is 340-380nm, the emission wavelength is 385-470nm, and collecting and arranging data.
As shown in FIG. 7, several drugs can significantly affect intracellular cholesterol levels at the corresponding concentrations. And The result is consistent with The result of a SOAT1 protein knock-down group (gene knock-down experiment, The expression of SOAT1 protein is interfered by sh-RNA which is purchased from sigma-aldrich company (http:// www.sigmaaldrich.com) in The USA, and The sequence of The SOAT1 sh-RNA is shown as 5'-CCGGTGGTCCATGACTGGCTATATTCTCGAGAATATAGCCAGTCATGGACCATTTTTTG-3'), which indicates that The drug targeting SOAT1 protein can cause The change of intracellular cholesterol.
In summary, the four disclosed drugs, Nilotinib (AMN-107), Ramipril (Altance), ABT-737, Evactrapib (LY2484595), bind to SOAT1 and thereby inhibit the conversion of cholesterol to cholesteryl esters, and increase intracellular cholesterol levels. They can obviously inhibit the growth of liver cancer cells and obtain IC superior to positive drug Avasimibe50Values (fig. 8). The invention provides a new liver cancer treatment targeted drug from the angle that targeted SOAT1 protein influences cholesterol steady state, and provides a new direction for clinical treatment of liver cancer.
Claims (10)
1. The application of the drug/compound targeting the SOAT1 protein in the preparation of the drug for preventing and/or treating liver cancer;
the drug/compound targeting the SOAT1 protein is selected from at least one of the following: nilotinib (AMN-107), Ramipril (Alpace), ABT-737 and Evactrapib (LY 2484595);
among them, Nilotinib (AMN-107), Cas No.: 641571-10-0, the structural formula is shown as follows:
ramipril (altace), Cas No.: 87333-19-5, the structural formula is shown as follows:
ABT-737, Cas No.: 852808-04-9, the structural formula is shown as follows:
evacetrrapib (LY2484595), CAS No.1186486-62-3, having the structural formula:
2. the use of the drug/compound targeting SOAT1 protein according to claim 1 in the preparation of inhibitors of liver cancer cell proliferation.
3. Use according to claim 2, characterized in that: the liver cancer cell is selected from any one of the following: HepG2, PLC and 97L.
4. Use according to claim 3, characterized in that: the Nilotinib (AMN-107) is used for treating the IC of three liver cancer cells HepG2, PLC/PRF/5 and MHCC97L50448.5nM, 15.7. mu.M and 2.44. mu.M, respectively, in that order;
the IC of Ramipril (Altace) for three liver cancer cells HepG2, PLC/PRF/5 and MHCC97L5096.8nM,25.1nM and 6.0. mu.M, respectively, in that order;
the IC of the ABT-737 to three hepatoma cells HepG2, PLC/PRF/5 and MHCC97L50184.0nM, 3.3. mu.M and 2.1. mu.M, respectively, in that order;
the IC of the Evacet rapib (LY2484595) on three liver cancer cells HepG2, PLC/PRF/5 and MHCC97L50This was followed by 9.2. mu.M, 5.6. mu.M and 2.0. mu.M, respectively.
5. Use according to any one of claims 2-4, characterized in that: the drug/compound targeting the SOAT1 protein is combined with the SOAT1 protein and influences the intracellular cholesterol homeostasis, so that the liver cancer cell proliferation is inhibited.
6. A product characterized by: the active ingredient of the product is at least one of Nilotinib (AMN-107), Ramipril (Alpace), ABT-737 and Evactrapib (LY 2484595).
7. The product of claim 6, wherein:
the product has at least one of the following effects:
1) for preventing and/or treating liver cancer;
2) inhibiting proliferation of hepatocarcinoma cell;
the product is a medicament or pharmaceutical formulation.
8. The use of the drug/compound targeting the SOAT1 protein of claim 1 in:
1) preventing and/or treating liver cancer;
2) inhibiting proliferation of hepatocarcinoma cell.
9. Use according to claim 6, characterized in that: the liver cancer cell is selected from any one of the following: HepG2, PLC/PRF/5 and MHCC 97L.
10. A method for preventing and/or treating liver cancer, comprising the steps of: administering a drug/compound targeting the SOAT1 protein according to claim 1 or a product according to claim 8 or 9 to a recipient animal or human for the prevention and/or treatment of liver cancer.
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| CN202210544982.5A CN114917345A (en) | 2021-04-07 | 2021-04-07 | Application of compound targeting SOAT1 protein in preparation of medicine for preventing and/or treating liver cancer |
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| CN115710301A (en) * | 2022-11-24 | 2023-02-24 | 陕西省中医药研究院 | SOAT1 protein targeted inhibitor and application |
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