CN114796234A - Application of cholesterol transport inhibitor U18666A as sensitizer in preparation of anti-tumor product - Google Patents
Application of cholesterol transport inhibitor U18666A as sensitizer in preparation of anti-tumor product Download PDFInfo
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- CN114796234A CN114796234A CN202210044410.0A CN202210044410A CN114796234A CN 114796234 A CN114796234 A CN 114796234A CN 202210044410 A CN202210044410 A CN 202210044410A CN 114796234 A CN114796234 A CN 114796234A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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Abstract
The invention relates to application of a cholesterol transport inhibitor U18666A as a sensitizer in preparation of an anti-tumor product. The invention discloses an application of combined medication of GPNA and U18666A in tumor resistance, wherein U18666A improves the killing effect of GPNA on tumor cells and provides a new method for overcoming the reduction of the antitumor effect of GPNA. The method specifically comprises the following steps: the GPNA and U18666A have better anti-tumor effect when being used together; U18666A increases the sensitivity of tumor cells to glutamine restriction; the combination of GPNA and U18666A can enhance the inhibition effect of GPNA on the proliferation of tumor cells; the combination of GPNA with U18666A significantly promoted tumor cell death. Compared with the prior art, the invention has more obvious anti-tumor effect.
Description
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to application of a cholesterol transport inhibitor U18666A as a sensitizer in preparation of an antitumor product, and application of a pharmaceutical composition of U18666A and GPNA in the antitumor product.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Malignant tumors are currently the major killers of human health and are among the most important diseases that severely threaten human life. Rapidly growing tumors are metabolically reprogrammed to produce sufficient structural molecules and energy. In normal cells, glutamine (Gln) is a non-essential amino acid. However, tumor cells need to provide a source of nutrients and energy for self-proliferation through Gln metabolism and help to scavenge ROS accumulated in tumor cells and maintain tumor cell redox homeostasis. Thus, Gln is an "essential amino acid" for tumors. Limiting Gln is a potential strategy for tumor therapy, where tumor cells can evade or reduce the damage that Gln deficiency causes to tumor cells through metabolic remodeling. GPNA (L-gamma-Glutamyl-p-nitroanilide) is a potent selective inhibitor of Gln transporter ASCT2(SLC1A5), and can remarkably reduce the intake of Gln. At present, the research finds that the effect of efficiently inhibiting the tumor growth cannot be achieved by singly using GPNA.
Remodeling of cholesterol metabolism is essential for the development of tumors. Many researches show that the cholesterol synthesis gene is highly expressed in tumors, and the tumor growth can be obviously inhibited by down regulating the key genes. Also, various drugs that inhibit cholesterol synthesis have been shown to inhibit tumor growth. However, the effect of intracellular cholesterol transport drugs on tumor cells is rarely reported. U18666A is an inhibitor of intracellular cholesterol transport, and has been reported to have significant inhibitory effects on viral infection and spread, and to cause tumor cell necrosis. On the basis of the medicine, the compound has potential application prospect when combined with other anti-tumor medicines.
The inventor considers that the tumor treatment effect of the Gln transporter inhibitor is insufficient, the corresponding sensitizer is developed, a combined medication strategy containing the Gln transporter inhibitor is provided, and the effective inhibition of tumor proliferation is expected to be realized.
Disclosure of Invention
The existing research proves that U18666A can inhibit the release of cholesterol from late endosomes and lysosomes, and has a remarkable influence on intracellular cholesterol transport pathways. Based on the inhibition of cholesterol transport by U18666A, the prior art also mimics the loss of functional Niemann-Pick type C protein, providing a corresponding disease model. U18666A subsequently became a tool to assess the importance of molecular trafficking through the lysosomal pathway in other conditions (e.g., atherosclerosis, Alzheimer's disease and viral infections). Since U18666A can limit cholesterol in membrane formation by inhibiting cholesterol synthesis and intracellular transport, the mechanisms of various processes in the body are widely affected. However, no relevant report exists for the application of U18666A in tumor resistance. In the invention, U18666A is used alone in vitro for tumor cells, and the effect of inhibiting tumor proliferation is not obvious.
GPNA is a Gln transport protein inhibitor, and the existing research proves that GPNA can promote pancreatic cancer cell apoptosis and improve breast cancer tamoxifen resistance and the like. In the invention, U18666A and GPNA are combined to be used in tumor cell culture and an in vivo mouse tumor model, research shows that the inhibition effect of the two compounds on tumor cells is remarkably improved after the two compounds are combined, and the research result shows that U18666A is expected to be used as a sensitizer to improve the anti-tumor effect of a Gln transport protein inhibitor.
Based on the research result of the invention, the invention firstly provides the application of the cholesterol transport inhibitor U18666A as a sensitizer in preparing an anti-tumor product.
Secondly, the invention also provides a novel treatment strategy of combined medication of GPNA and U18666A, and particularly provides a form of a pharmaceutical composition, which effectively inhibits the proliferation of tumor cells and promotes the death of the tumor cells.
Based on the pharmaceutical composition, the invention also correspondingly provides the anti-tumor application of the pharmaceutical composition, in particular the application in the aspect of resisting liver cancer.
The beneficial effects of one or more technical schemes are as follows:
in one embodiment of the invention, U18666A is provided as a sensitizer for anti-tumor application, and a GPNA and U18666A composition form is further provided, the tumor inhibition effect of the drug combination is remarkably improved, and a drug administration mode with simple cost and remarkable curative effect is expected to be provided for clinical drug administration.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a graph showing the in vitro staining of GPNA in combination with U18666A with crystal violet;
FIG. 2 is a statistical chart of in vitro crystal violet staining of combinations of GPNA and U18666A;
FIG. 3 is a PI fluorescence plot of the in vitro combination of GPNA and U18666A;
FIG. 4 is a PI positive statistical chart of the in vitro combination of GPNA and U18666A;
FIG. 5 is a graph of the change in tumor volume for the combination of GPNA and U18666A in vivo;
FIG. 6 is a graphical representation of the in vivo combination of GPNA with U18666A, Ki 67;
FIG. 7 is a group statistical chart of Ki67 in combination of GPNA and U18666A in vivo.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As described in the background, selective inhibitors of the Gln transporter ASCT2(SLC1A5) may be useful in inhibiting tumor cell growth by reducing the uptake of Gln into the cell, but such inhibitors are not ideal when used alone. In order to solve the technical problems, the invention provides application of U18666A as a GPNA sensitizer, and better anti-tumor effect can be achieved by using the sensitizer as a medicine combination.
The invention provides an application of a cholesterol transport inhibitor U18666A as a sensitizer in preparation of an anti-tumor product.
The structural formula of U18666A in the first aspect is C 25 H 42 ClNO 2 CAS number: 3039-71-2.
In a second aspect of the present invention, a pharmaceutical composition is provided, which comprises at least one cholesterol transport inhibitor and one Gln transporter inhibitor.
In one embodiment of the pharmaceutical composition of the second aspect, the cholesterol transport inhibitor is U18666A and the Gln transporter inhibitor is GPNA. In the above embodiments, the ratio of the two compounds can be determined according to routine studies in the art, and can be determined in a feasible manner, such as MTT and the like. In a feasible mode provided by the invention, the mass ratio of the GPNA to the U18666A is 20: 1-5; further, the mass is 20: 2-3; specific mass ratios such as 20: 2 or 20: 2.5 or 20: 3.
the dosage form of the pharmaceutical composition of the second aspect is not particularly limited, and possible formulation forms include solid formulations (tablets, capsules, granules, powders, etc.), liquid formulations (syrups, injections, etc.), and the like; in addition, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, and various organic or inorganic carrier materials generally used as pharmaceutical materials may be used as the carrier.
Possible carriers in the above solid preparations include excipients, lubricants, binders, disintegrators, etc.;
in liquid formulations, the carrier includes solubilizers, suspending agents, isotonic agents, buffers, soothing agents. Preservatives, antioxidants, colouring agents, sweeteners and other formulation additives may also be included, as appropriate.
In a third aspect of the present invention, there is provided a use of the pharmaceutical composition of the second aspect in the preparation of an anti-tumor product.
The application mode includes but is not limited to any one of the following modes:
(1) the pharmaceutical composition is applied to medicines, health products or special medical foods for treating and preventing/treating tumors;
(2) the pharmaceutical composition is used as a model medicament, and the model medicament is used for preparing tumor growth inhibition models and the like.
In a fourth aspect of the present invention, there is provided an antitumor agent, wherein the pharmaceutical composition of the first aspect is used as an active ingredient.
In an embodiment of the anti-tumor drug according to the fourth aspect, the pharmaceutical composition is used as the sole active ingredient, and in this embodiment, the anti-tumor drug is composed of a pharmaceutical composition and a pharmaceutical carrier.
In another embodiment, the antitumor drug further comprises an active ingredient in addition to the pharmaceutical composition of the second aspect; the other active ingredients include, but are not limited to, cytotoxic drugs, nucleic acid synthesis, transcription inhibitors, hormonal drugs, monoclonal antibodies, interferons, or biological response modifiers, and the like.
The tumor is one of brain tumor, oral tumor, lung cancer, gastric cancer, liver cancer, intestinal cancer, uterine tumor, osteosarcoma or glioma; in one possible embodiment of the present invention, the anti-tumor drug is an anti-liver cancer drug.
In a fifth aspect of the present invention, there is provided a method for treating tumors, which comprises administering the pharmaceutical composition of the second aspect, or the antitumor agent of the fourth aspect, to an individual in need thereof.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
The cell lines and animals referred to in the following examples are as follows:
the human hepatoma cell line HepG2 was purchased from Shanghai Zhongji cell institute; mouse hepatoma carcinoma cell H22 was purchased from Shandong institute of medicine; SPF-grade BALB/c-nu nude mice, female mice, 10 mice, 6-8 weeks old and 18-20g of body weight, Beijing Wittingle laboratory animal technology Limited company, the production license code of the laboratory animal is SCXK (Jing) 2016-.
The following examples refer to the drugs and the main agents as follows:
GPNA: seleckk Corp
U18666A: MCE Corp Ltd
High-quality Fetal Bovine Serum (FBS), DMEM medium, and pancreatin: thermo Co Ltd
Rabbit anti-Ki67 antibody：Abcam
Goat anti-Rabbit IgG(H+L)HRP：Abways
Combining pen and DAB color developing solution: china fir gold bridge
Hematoxylin: biometrics bioengineering (Shanghai) Ltd
Crystal violet reagent: sigma Co Ltd
Propidium Iodide (PI): biyuntian (a Chinese character)
The main instruments involved in the following examples are as follows:
a liquid transfer device: eppendorf Co Ltd
Medical centrifuge, available from Shandong Bai Europe medical science and technology Limited
Carbon dioxide cell incubator: panasonic corporation
The biological safety cabinet: thermo Co Ltd
Inverted fluorescence microscopy: olympus Corp
A constant-temperature water bath kettle: jinghong Co Ltd
Paraffin slicer: thermo Corp Ltd
Example 1
1. Cell culture
Human hepatocellular carcinoma HepG2 cell line was cultured in DMEM medium containing 100U/mL streptomycin, 100U/mL penicillin and 10% bovine serum, and placed in 5% CO 2 Culturing at constant temperature of 37 ℃ under saturated humidityAnd (5) performing aseptic culture in a box.
2. Cell crystal violet staining experiment
HepG2 cells expressed 1x 10 5 Inoculating to 24-well plate, and culturing at 37 deg.C overnight; the culture medium was changed in the following order, no drug was added to the control group, GPNA (0.5mM), U18666A (1. mu.M), GPNA (0.5mM) and U18666A (1. mu.M) were added to the experimental group in the order, and the culture was carried out at 37 ℃ for 24 hours; removing the culture medium by suction, adding 500 μ L of precooled PBS, removing by suction, adding 500 μ L of methanol, and fixing at room temperature for 10 min; removing methanol by suction, adding 500 μ L crystal violet staining solution (0.5%), and staining for 15min at room temperature; sucking away the staining solution, washing the residual staining solution with tap water, naturally drying, and observing and taking a picture under a microscope.
3. Effect of drugs on cell proliferation
As can be seen from FIGS. 1 and 2, the treatment with 0.5mM GPNA has the effect of inhibiting the proliferation of tumor cells, the inhibition effect is 25%, 1 μ M U18666A does not affect the proliferation process of tumor cells basically, the combination of the two drugs can significantly inhibit the proliferation of tumor cells, and the inhibition efficiency is about 2.7 times that of the treatment with 0.5mM GPNA alone compared with the control group.
4. Cellular PI staining experiments
HepG2 cells expressed 1x 10 5 Inoculating to 24-well plate, and culturing at 37 deg.C overnight; the culture medium was changed in the following order, no drug was added to the control group, GPNA (0.5mM), U18666A (1. mu.M), GPNA (0.5mM) and U18666A (1. mu.M) were added to the experimental group in the order, and the culture was carried out at 37 ℃ for 24 hours; PI staining solution (1. mu.g/mL) was added, and after staining for 2min at room temperature, photographs were taken under a microscope.
5. Effect of drugs on cell death
As can be seen from fig. 3 and 4, the total number of cells varied in accordance with the results of fig. 1 and 2. In addition, the treatment of 0.5mM GPNA has the effect of promoting the death of tumor cells compared with the control group, and the PI positive rate of the GPNA treatment group is 12 times higher than that of the control group; meanwhile, the 1 mu M U18666A treatment has low toxicity to tumor cells and has no significant influence on cell proliferation and death; when 0.5mM GPNA was used in combination with 1. mu. M U18666A, the tumor cell death rate was 33-fold higher than that of the control group, which was approximately 21-fold higher than that of the group treated with 0.5mM GPNA alone, indicating that U18666A significantly enhanced the tumor-suppressing effect of GPNA. Thus, 1 μ M U18666A in combination with 0.5mM GPNA is a more optimal anti-tumor strategy.
Example 2
1. Animal model establishment and grouping
The H22 cells are revived in ascites of mice, and 0.1mL/5x10 cells are respectively taken under the aseptic condition 5 The injection is injected to the left and right sides of the back of the mouse subcutaneously, and after the tumor modeling is successful, the injection is randomly divided into four groups, including a blank control group, a GPNA treatment group, a U18666A treatment group and a combination treatment group of GPNA and U18666A.
The administration mode and route of the different administration groups are shown in table 1, and the blank control group is administered with the same amount of PBS.
TABLE 1 modes and routes of administration for different experimental groups
Note: i.p.: intraepithelial injection, i.e. intraperitoneal injection; qd: quadure die, once a day
2. Tumor volume determination
The major diameter (L) and the minor diameter (W) of the tumor nodules of each group of animals were measured with a vernier caliper, the tumor volumes were calculated according to the elliptic volume formula (V. L. W2/2) and averaged for each group, and the relative proliferation rates of the tumor volumes of each group were compared with each other, which was Day n/Day 1.
3. Effect of drugs on tumor volume
After the H22 subcutaneous tumor model was prepared, tumor volumes were determined using GPNA alone, U18666A alone, and GPNA in combination with U18666A, respectively. As shown in fig. 5, U18666A treatment alone reduced tumor growth compared to the control group, but was not statistically significant; GPNA alone treatment significantly inhibited tumor growth compared to controls; the combination of GPNA with U18666A significantly inhibited tumor growth compared to control or any drug alone, particularly emphasizing that the use of U188666A significantly increased tumor inhibition efficiency of GPNA. Thus, the above results indicate that U18666A increases the sensitivity of tumor tissue to glutamine restriction.
4. Preparation of tissue embedding and Paraffin sectioning
(1) Placing the tissue to be embedded into a 5mL centrifuge tube containing 4% paraformaldehyde, and fixing for 24 h;
(2) taking out the tissue, placing the tissue into an embedding box, moving the tissue into a dehydrator, and performing dehydration and hardening according to the procedure shown in the table 2;
TABLE 2 dehydration hardening procedure
(3) After the above steps were completed, the tissue was placed in an iron box for embedding and immersed in molten paraffin, covered with the embedding box, and placed on ice until it solidified.
(4) After the tissue wax block is solidified, taking down the tissue wax block from an iron box, fixing the tissue wax block on a paraffin slicer, mounting a blade, modifying the tissue wax block with the thickness of 20 microns until the tissue is exposed, then cutting off a wax sheet with the thickness of 3 microns and with the tissue, placing the wax sheet in water at 45 ℃, after the wax block is stretched, lightly picking up the wax block by using a glass slide to enable the wax block to be flatly covered on the glass slide, then placing the glass slide on a grill at 65 ℃, baking the glass slide for 2 hours, and then taking the glass slide into a glass slide box for subsequent experiments.
5. Immunohistochemical staining of paraffin sections
The tumor tissue slices are placed in a 65 ℃ oven to be baked for 2 hours;
gradient dewaxing hydration:
xylene (2 times, 15 min/time); 100% ethanol (2 times, 5 min/time); 90% ethanol (1 time, 5 min/time); 70% ethanol (1 time, 5 min/time); distilled water (1 time, 5 min/time);
performing antigen retrieval by using EDTA antigen retrieval solution (stock solution of EDTA antigen retrieval solution: distilled water: 1: 50);
and (3) putting 600mL of antigen repairing solution into a 1000mL glass beaker, putting the glass rack into a microwave oven, heating the glass rack for 8min by high fire until the liquid is boiled, then continuously heating the glass rack for 10min by medium and high fire, and taking the beaker out of a fume hood after heating and cooling the beaker to room temperature.
Placing the slices in a wet box, circling out the tissues by using a tissue pencil, dripping a primary antibody solution diluted according to a certain proportion, and incubating for 2 hours at room temperature.
Rinse 3 times 5min each time on a shaker with 1XPBST solution (containing 0.1% Tween 20).
And (4) dropwise adding a diluted secondary antibody solution in a certain proportion, and incubating for 30min at room temperature.
The 1XPBST rinse was performed 3 times, 5min each time.
According to the liquid B: and C, preparing a DAB color developing solution according to the proportion of 50:1, dripping the DAB color developing solution on the tissue, putting the tissue into tap water to stop dyeing when positive dyeing is found under a mirror, and keeping the DAB dyeing time of the same tissue section consistent.
The staining is stopped by tap water after hematoxylin staining for 2-5 min.
The rinsing with 1% hydrochloric acid alcohol was performed for 1s, and the rinsing with tap water was stopped.
Gradient alcohol elution: 70% ethanol (5min), 90% ethanol (5min), 100% ethanol (5min), and xylene (10 min).
And (4) drying the dyed slices, dripping neutral gum, and sealing the slices by a cover glass.
6. Drug inhibition of tumor cell proliferation
By combining the graphs of fig. 6 and fig. 7, Ki67 group staining is carried out on tumor tissues, the positive rate of Ki67 in the tumor tissues without drug treatment is higher, the positive rate of Ki67 is reduced after GPNA treatment, the inhibition effect of the U18666A on tumor proliferation is not obvious when the U18666A is used alone, but the positive rate of Ki67 can be obviously reduced when the U18666A is used in combination with GPNA, which indicates that the sensitivity of tumors to GPNA drugs can be obviously enhanced, and the combination of the GPna and the U18666A is a better in-vivo anti-tumor strategy.
7. Statistical analysis
Statistical processing was performed using GraphPrism software, and the data was expressed as mean ± SD, and two or more comparisons were performed using one-way ANOVA, and between groups using t-test, pvalware as GP:0.1234(ns),0.0332(, 0.0021(, 0.0002(, x)), and <0.0001(, x). The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The application of cholesterol transport inhibitor U18666A as sensitizer in preparation of anti-tumor products is characterized in that the structural formula of U18666A is C 25 H 42 ClNO 2 CAS number: 3039-71-2.
2. A pharmaceutical composition comprising at least one cholesterol transport inhibitor and at least one Gln protein transport inhibitor.
3. The pharmaceutical composition of claim 2, wherein the cholesterol transport inhibitor is U18666A and the Gln protein transport inhibitor is GPNA.
4. The pharmaceutical composition of claim 3, wherein the mass ratio of GPNA to U18666A is 20: 1-5;
further, the mass is 20: 2-3; specific mass ratios such as 20: 2 or 20: 2.5 or 20: 3.
5. the pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in a form of a solid formulation or a liquid formulation; also comprises a pharmaceutically acceptable carrier;
the carrier of the solid preparation comprises excipient, lubricant, adhesive or disintegrant;
the carrier of the liquid preparation comprises a solubilizer, a suspending agent, an isotonic agent, a buffering agent and a soothing agent; preservatives, antioxidants, colouring agents, sweeteners and other formulation additives are also suitably included.
6. Use of a pharmaceutical composition according to any one of claims 2 to 5 for the preparation of an anti-tumor product.
7. The use of the pharmaceutical composition of claim 6 for the preparation of an anti-tumor product by means including, but not limited to, any one of the following:
(1) the pharmaceutical composition is applied to medicines, health products or special medical foods for treating and preventing/treating tumors;
(2) the pharmaceutical composition is used as a model medicament for preparing a tumor growth inhibition model.
8. An antitumor agent characterized in that the pharmaceutical composition according to any one of claims 2 to 5 is used as an active ingredient in the agent.
9. The antitumor agent as claimed in claim 8, wherein said antitumor agent is composed of a pharmaceutical composition and a pharmaceutical carrier;
or, the anti-tumor medicament also comprises other active ingredients; the other active ingredients are drugs including but not limited to cytotoxic drugs, nucleic acid synthesis, transcription inhibitors, hormonal drugs, monoclonal antibodies, interferons or biological response modifiers;
or, the tumor is one of brain tumor, oral tumor, lung cancer, gastric cancer, liver cancer, intestinal cancer, uterine tumor, osteosarcoma or glioma; furthermore, the anti-tumor drug is a liver cancer resistant drug.
10. A method for treating tumors, which comprises administering the pharmaceutical composition of any one of claims 2 to 5 or the antitumor agent of claim 8 or 9 to an individual in need thereof.
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| US20210154162A1 (en) * | 2018-03-02 | 2021-05-27 | Institute Of Basic Medical Sciences Chinese Academy Of Medical Sciences | Drug and pharmaceutical composition containing transport protein inhibitor, and use |
| US20210263039A1 (en) * | 2017-06-15 | 2021-08-26 | Beijing Proteome Research Center | Application of niemann-pick c1 protein in diagnosis and treatment of cancer |
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| US20210154162A1 (en) * | 2018-03-02 | 2021-05-27 | Institute Of Basic Medical Sciences Chinese Academy Of Medical Sciences | Drug and pharmaceutical composition containing transport protein inhibitor, and use |
| CN110003303A (en) * | 2019-05-07 | 2019-07-12 | 河南农业大学 | The anti-viral uses of cholesterol transport inhibitor |
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