CN116650478A - Application of KY1220 in preparation of drug for inhibiting mycobacterium tuberculosis - Google Patents
Application of KY1220 in preparation of drug for inhibiting mycobacterium tuberculosis Download PDFInfo
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- CN116650478A CN116650478A CN202310408639.2A CN202310408639A CN116650478A CN 116650478 A CN116650478 A CN 116650478A CN 202310408639 A CN202310408639 A CN 202310408639A CN 116650478 A CN116650478 A CN 116650478A
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- tuberculosis
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- mycobacterium tuberculosis
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Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the technical field of medicines, and provides an application of a small molecular compound in preparing an anti-mycobacterium tuberculosis preparation, wherein the small molecular compound is KY1220 or a composition containing KY 1220; the composition containing the KY1220 is a composition containing the KY1220 and other active ingredients, wherein the other active ingredients are active substances capable of promoting the anti-tuberculosis of the organism and/or medicines for improving tuberculosis symptoms. The invention uses KY1220 to show good antibacterial activity on mycobacterium tuberculosis, and can obviously inhibit mycobacterium tuberculosis. In addition, KY1220 has a relatively high survival rate for U937 and THP-1 cells.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a small molecular compound KY1220 in preparation of a medicine for inhibiting mycobacterium tuberculosis.
Background
Tuberculosis (TB) is one of the most global mortality of human chronic infections caused by mycobacterium tuberculosis (Mycobacterium tuberculosis, mtb), one of the major challenges facing global public health, the "first killer" of aids virus (human immunodeficiency virus, HIV) infected persons, the main lethal infectious disease associated with antibiotic resistance, and the mortality rate is very high among HIV carriers simultaneously infected with multi-drug resistant mycobacterium tuberculosis, which is also the cause of the epidemic of multi-drug resistant tuberculosis. According to the world health organization estimates, over 1060 ten thousand new tuberculosis patients worldwide in 2021 and over 160 ten thousand deaths, only 36% of patients needing treatment are treated, and the epidemic of drug-resistant strains and the combined infection of HIV further aggravate the burden of global TB. The number of patients with rifampicin resistant tuberculosis (rifampicin resistance-tuberculosis, RR-TB) and multi-drug resistant tuberculosis (multiple drug resistant tuberculosis, MDR-TB) beginning to be treated in 2021 is 161 and 746, only 1/3 of all patients in need of treatment are covered, and 18.7 ten thousand of HIV-infected patients die from tuberculosis, so that effective control of tuberculosis is still a major public health challenge facing the world.
Although the development and advancement of drugs for the treatment of tuberculosis continue to be ongoing, there is always active development of a vaccine effective against the transmission of mycobacterium tuberculosis worldwide, it is challenging to develop a new vaccine that is more adaptable and durable than BCG (Bacillus Calmette Guerin, BCG). Mycobacterium tuberculosis has the ability to regulate host immune response and evade drugs, which can lead to failure of BCG vaccination and finally form drug-resistant Mycobacterium tuberculosis.
In recent years, great progress has been made in tuberculosis treatment, such as Isoniazid (INH), rifampicin (RFP), bedaquiline, delamanib, etc. are very effective against mycobacterium tuberculosis, but it is still impossible to treat tuberculosis thoroughly, and INH is resistant, which usually results in the emergence of multi-drug resistant strains, thus becoming a major obstacle to controlling tuberculosis, bedaquiline and delamanib have limited activity of killing persisters, and both drugs have strong cardiotoxicity, and more importantly, mycobacterium tuberculosis mutant strains with resistance to both drugs are rapidly found in clinic. Fluoroquinolones are effective two-wire antitubercular drugs for treating drug-resistant tuberculosis, and are widely used for treating multi-drug-resistant tuberculosis, but fluoroquinolones are found to be easy to resist in the treatment of multi-drug-resistant tuberculosis, and although fluoroquinolones have a good inhibition effect on DNA gyrase, mutation of gyrA structural domain generates drug resistance to the drugs in the treatment process of tuberculosis. With the advent of drug resistance in mycobacterium tuberculosis, new therapies that can shorten the treatment cycle are critical to the prevention and treatment of tuberculosis, and in particular, some therapies with new mechanisms of action provide effective methods for the treatment of drug resistant tuberculosis.
Based on the above problems, the urgent need to develop a novel tuberculosis inhibiting drug with high efficiency and low toxicity to effectively control tuberculosis has become an important research direction for many researchers.
Disclosure of Invention
In a first aspect, the invention provides the use of a small molecule compound for the preparation of an anti-mycobacterium tuberculosis formulation.
Further, the small molecule compound is KY1220 or a composition containing KY 1220.
Further, the structural formula of KY1220 is shown as I:
further, the composition containing KY1220 is a composition containing KY1220 and other active ingredients.
Further, the other active ingredients are active substances capable of promoting the anti-tuberculosis of the body and/or medicines for improving tuberculosis symptoms.
Further, the formulation may be a biological or pharmaceutical formulation.
Further, the anti-mycobacterium tuberculosis preparation formulation comprises: sugar-coated tablet, film-coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, buccal preparation, granule, pill, pellet, suspension, powder, medicated wine, preparation, drop, injection, powder for injection, cream, sustained release preparation, targeting agent, etc.
Further, the administration mode of the anti-mycobacterium tuberculosis preparation comprises oral administration, injection, implantation, external application, spraying and inhalation.
Further, the anti-mycobacterium tuberculosis preparation can be applied to prevention or treatment of tuberculosis caused by mycobacterium tuberculosis infection.
Further, the mycobacterium tuberculosis infection comprises: primary infection, secondary infection, and extrapulmonary infection.
Further, the tuberculosis includes, but is not limited to, drug-resistant tuberculosis, non-drug-resistant tuberculosis, pulmonary tuberculosis, extrapulmonary tuberculosis, etc.
Further, the drug-resistant tuberculosis includes, but is not limited to, single-resistant tuberculosis, multi-resistant tuberculosis, and widely-resistant tuberculosis.
Further, the tuberculosis includes, but is not limited to, primary tuberculosis, secondary tuberculosis, blood group disseminated tuberculosis, tracheal-bronchial tuberculosis, tuberculous pleurisy, mycoyin tuberculosis, etc.
Further, the extrapulmonary tuberculosis includes, but is not limited to, intestinal tuberculosis, renal tuberculosis, bone joint tuberculosis, etc.
In a second aspect, the present invention provides the use of a compound according to the first aspect for the preparation of an anti-tuberculosis formulation.
Further, the small molecule compound is KY1220 or a composition containing KY 1220.
Further, the structural formula of KY1220 is shown as I:
further, the combination of KY1220 is a composition comprising KY1220 and other active ingredients.
Further, the other active ingredients are active substances capable of promoting the anti-tuberculosis of the body and/or medicines for improving tuberculosis symptoms.
Further, the formulation may be a biological or pharmaceutical formulation.
Further, the anti-tuberculosis formulation and/or the pharmaceutical dosage form comprises: sugar-coated tablet, film-coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, buccal preparation, granule, pill, pellet, suspension, powder, medicated wine, preparation, drop, injection, powder for injection, cream, sustained release preparation, targeting agent, etc.
Still further, the mode of administration of the antitubercular drug includes oral administration, injection, implantation, external use, spraying, inhalation and/or combinations thereof.
Further, the tuberculosis includes, but is not limited to, drug-resistant tuberculosis, non-drug-resistant tuberculosis, pulmonary tuberculosis, extrapulmonary tuberculosis, etc.
Further, the drug-resistant tuberculosis includes, but is not limited to, single-resistant tuberculosis, multi-resistant tuberculosis, and widely-resistant tuberculosis.
Further, the tuberculosis includes, but is not limited to, primary tuberculosis, secondary tuberculosis, blood group disseminated tuberculosis, tracheal-bronchial tuberculosis, tuberculous pleurisy, mycoyin tuberculosis, etc.
Further, the extrapulmonary tuberculosis includes, but is not limited to: tuberculosis of intestine, renal tuberculosis, bone joint tuberculosis, etc.
Drawings
FIG. 1 shows the MIC detection results of KY1220 acting on a Mycobacterium tuberculosis standard strain and drug-resistant Mycobacterium tuberculosis
FIG. 2 shows the survival rate of KY1220 against both U937 and THP-1 cells
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to limit the invention, so that those skilled in the art may better understand the invention and practice it. The experimental procedures in the examples, unless otherwise specified, all employ techniques conventional in the art and the experimental reagents are commercially available.
KY1220 has a chemical structural formula shown as I:
is a small molecule compound, can target the Wnt/beta-catenin pathway to destroy the stability of beta-catenin and Ras, and inhibit a series of reactions including Epithelial-mesenchymal transition (EMT) and apoptosis. Aberrant activation of Wnt/β -catenin and the Ras pathway was found to be associated with metastatic colorectal cancer and to be synergistic in tumor metastasis, while KY1220 disrupts the binding affinity of Ras to the β -catenin complex by binding to the G protein signaling domain (Regulator ofG protein Signaling, RGS) domain of axin, resulting in β -catenin and Ras being activated by gsk3β while losing stability, a mechanism of action that is an ideal strategy for the treatment of metastatic colorectal cancer.
Cell lines: the standard strain H37Rv of the mycobacterium tuberculosis is from cell bank (ATCC: 27294), the drug-resistant strain 2 is MDR-1, the MDR-2 is from clinical isolates of Beijing thoracic hospital (MDR-1 strain is resistant to rifampicin, isoniazid and streptomycin; MDR-2 strain is resistant to rifampicin, isoniazid, streptomycin and ethambutol), human histiocyte lymphoma cells (U937 cells) and human monocyte leukemia cells (THP-1 cells).
Tuberculosis with single drug resistance: the single drug resistance refers to mycobacterium tuberculosis infected by tuberculosis patients, and the drug resistance to an antituberculosis drug is proved by in vitro.
Multi-drug resistant tuberculosis: the multi-drug resistance refers to the fact that the mycobacterium tuberculosis infected by tuberculosis patients is proved to be resistant to more than one antitubercular drug in vitro, but does not comprise the condition of simultaneous resistance to isoniazid and rifampicin.
Multi-drug resistant tuberculosis: tuberculosis that is resistant to isoniazid and rifampicin at the same time is called multi-drug resistant tuberculosis.
Based on multi-drug resistant tuberculosis, the drug is resistant to fluoroquinolones and two-line injection antitubercular drugs, including one drug resistant from kanamycin, amikacin, frizzled mycin and streptomycin, and the drug resistant tuberculosis is called as the wide drug resistant tuberculosis.
EXAMPLE 1KY1220 in vitro drug sensitivity test against tubercle bacillus
The activity of KY1220 in vitro anti-tuberculosis mycobacterium standard strain H37Rv is determined by adopting a 96-well plate micro-dilution method.
200. Mu.L of sterile PBS was added to the sterile 96-well plate in two surrounding circles to prevent evaporation. 120. Mu.L of 7H9 liquid medium containing 10% OADC (except for rows A and H) was added to the C3 and D3 wells, 100. Mu.L of 7H9 liquid medium containing 10% OADC was added to the remaining C4-C10 wells, 80. Mu.L of KY1220 (powder dissolved in DMSO and frozen at-80 ℃) diluted to 100. Mu.M was added to the C3 and D3 experimental wells, 100. Mu.L of liquid in the 3 rd well was pipetted into the 4 th well after being blown uniformly, and then the above procedure was continued until all of the drugs were diluted to a final concentration of 20. Mu.M, 10. Mu.M, 5. Mu.M, 2.5. Mu.M, 1.25. Mu.M, 0.625. Mu.M, 0.312. Mu.M, 0.156. Mu.M (200. Mu.L volume) was completed. To the E-line positive drug wells, INH at a final concentration of 1. Mu.g/ml and RIF stock at 0.1. Mu.g/ml were added, and 4 multiplex wells were set up, respectively. 200. Mu.L of 7H9 liquid medium containing 10% OADC was added to the F3-F6 row as a negative control well, and 100. Mu.L of 7H9 liquid medium containing 10% OADC was added to the F7-F10 row as a positive control well (see Table 1).
TABLE 1 concentration profiles of MTB Standard 96 well plates
The activity of KY1220 on drug-resistant strains MDR-1 and MDR-2 is measured by a 96-well plate micro dilution method.
200 μl of sterile PBS (to prevent evaporation) was added around the sterile 96-well plate, 120 μl of 7H9 liquid medium containing 10% OADC was added to each of B2, C2, D2, E2 wells, 100 μl of 7H9 liquid medium containing 10% OADC was added to each of the remaining wells, and 80 μl of KY1220 stock solution (lyophilized powder dissolved in DMSO at-80deg.C) diluted to a concentration of 100 μM was added to each of B2, C2, D2, E2 wells. The liquid in the holes B2, C2, D2 and E2 is blown evenly by a liquid transfer device, 100 mu L of the liquid is sucked into the corresponding hole in the 3 rd row, and then the blowing evenly is continued and the operation is repeated until the corresponding hole in the 9 th row is completed until all the medicines are diluted, so that the final medicine concentration is 20 mu M, 10 mu M, 5 mu M, 2.5 mu M, 1.25 mu M, 0.625 mu M, 0.312 mu M and 0.156 mu M (200 mu L volume). B2-11/C2-11 is MDR-1 group, D2-11/E2-11 is MDR-2 group. Column 12 was further supplemented with 100. Mu.L of 7H9 liquid medium containing 10% OADC as negative control wells, column 10 as positive control wells, and 2 wells for positive control of 2 drug-resistant bacteria (see Table 2).
TABLE 2 concentration profiles of MTB resistant strain 96 well plates
The two MTB strain's Roche culture media cultured to logarithmic growth phase are taken out from a constant temperature incubator at 37 ℃, bacterial colonies are scraped respectively and are put into a 2mL ultrasonic dispersion tube containing l0% OADC 7H9 liquid culture media, ultrasonic is carried out for 1min in an ultrasonic dispersion instrument, the ratio of bacterial liquid to liquid culture media is adjusted in a cuvette, the mixture is placed in a spectrophotometer, the detection wavelength is set to 600nm, the absorbance value of each strain is adjusted to 0.3, and the concentration of bacterial liquid of each strain is calculated according to the absorbance value. Then diluting the two bacterial solutions by 10 times with 7H9 liquid culture medium, respectively sucking 100 mu L of diluted bacterial solutions with a pipettor, adding into two 96-well plates, sealing the sterile 96-well culture plates with the bacterial solutions with sealing films, and placing in a constant temperature incubator at 37 ℃ for static culture for 10 days.
After 10 days, the two 96-well plates were removed from the incubator, the sealing film was carefully removed in a biosafety cabinet, and 70 μl of resazurin indicator was added to each well. The sterile 96-well culture plate added with the indicator is placed in a constant temperature incubator at 37 ℃ for standing and incubation for 24-48h.
At the end of incubation, the two 96-well plates were removed, the color change of each well site in the two 96-well plates (blue for sterile strain growth, pink for strain growth) was observed and recorded, and the MIC (minimum inhibitory concentration was defined as the minimum drug concentration that inhibited visible growth of bacteria). MIC values were defined as drug concentration values at which the 96-well plate changed from blue to pink after addition of the resazurin indicator for 24-48 hours after incubation in a 37 ℃ incubator for 10 days, pink indicating bacterial growth.
Graphpad8.0.2 software was used to plot and statistically analyze the results.
The experimental results show that KY1220 has an MIC of 2.5 mu M for MTB H37Rv and 10 mu M for 2 clinical multi-drug resistant bacteria MDR1 and MDR1 strains, and the KY1220 has good inhibition effect on mycobacterium tuberculosis in vitro (see figure 1).
EXAMPLE 2KY1220 test for inhibiting Mycobacterium tuberculosis cytotoxicity
The invention adopts the CCK-8 method to determine the cell survival rate, the CCK-8 method utilizes the WST-8[ (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazolium monosodium salt ], and the CCK-8 method can be reduced into water-soluble orange yellow formazan dye by dehydrogenase in mitochondria of living cells under the action of electronic carrier 1-methoxy-5-methylphenazine dimethyl sulfate, and the quantity of formazan generated is in direct proportion to the quantity of the living cells.
Frozen human tissue cell lymphoma cells (U937 cells) and human monocytic leukemia cells (THP-1 cells) were removed from liquid nitrogen, resuscitated and cultured to logarithmic phase, the cell suspension concentration was adjusted to about 2X 105 cells/mL, added to 96-well cell culture plates at 100. Mu.L per well, and Phorbol 12-myristate 13-acetate, PMA was added to differentiate the cells into macrophages at a final concentration of 50ng/mL in a cell culture incubator (5% CO) 2 Incubated overnight at 37 ℃. The old medium was then aspirated and medium was added to the plates to dilute KY1220 at final concentrations of 20. Mu.M, 10. Mu.M, 5. Mu.M, 2.5. Mu.M, 1.25. Mu.M, 2 wells per concentration. The negative control wells contained no drug and the cell plates were placed in an incubator for further incubation for 24h. The medium was then aspirated and the medium was proliferated/fine according to CCK-8 cellsCytotoxicity kits (cat# CK04, japanese Kogyo chemical institute) were used to detect cytotoxicity of drugs.
The experimental results showed that the viability of U937 and THP-1 cells at a concentration of KY1220 of 20. Mu.M was 107.6% and that of U937 and THP-1 cells at a concentration of 2.5. Mu.M was 109.2% and that of 92.0%, respectively, and that there was no statistical difference in cell viability compared to the control group when the drug concentration was 20. Mu.M and 2.5. Mu.M (see FIG. 2).
In conclusion, the experimental result shows that KY1220 shows good antibacterial activity on mycobacterium tuberculosis and can remarkably inhibit the mycobacterium tuberculosis. In addition, KY1220 has a relatively high survival rate for U937 and THP-1 cells. Therefore, KY1220 can be used for preparing medicines for resisting mycobacterium tuberculosis.
Claims (10)
1. The application of a small molecular compound in preparing an anti-mycobacterium tuberculosis preparation, wherein the small molecular compound KY1220 or a composition containing the KY1220 is shown in the specification, and the structural formula of the small molecular compound KY1220 is shown in the specification:
2. the use of a small molecule compound according to claim 1 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein the composition comprising KY1220 is a composition comprising KY1220 and other active ingredients.
3. Use of a small molecule compound according to claim 1 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein the additional active ingredient is an active substance that promotes anti-tuberculosis in the body and/or is a drug that ameliorates the symptoms of tuberculosis.
4. Use of a small molecule compound according to claim 1 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein the formulation comprises a biological or pharmaceutical formulation.
5. The use of a small molecule compound according to claim 1 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein said anti-mycobacterium tuberculosis formulation comprises: sugar-coated tablet, film-coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, buccal preparation, granule, pill, pellet, suspension, powder, medicated wine, preparation, drop, injection, powder for injection, cream, sustained release agent, and targeting agent.
6. The use of a small molecule compound according to claim 1 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein the anti-mycobacterium tuberculosis formulation is useful for the prevention or treatment of tuberculosis caused by mycobacterium tuberculosis infection.
7. The use of a small molecule compound according to claim 1 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein said mycobacterium tuberculosis infection comprises: primary infection, secondary infection, and extrapulmonary infection.
8. The use of a small molecule compound according to claim 6 for the preparation of an anti-mycobacterium tuberculosis formulation, wherein said tuberculosis includes, but is not limited to, drug-resistant tuberculosis, non-drug-resistant tuberculosis, pulmonary tuberculosis, extrapulmonary tuberculosis.
9. The use of a small molecule compound according to claim 8 for the preparation of an anti-mycobacterium tuberculosis formulation, said tuberculosis including, but not limited to, primary tuberculosis, secondary tuberculosis, blood group-disseminated tuberculosis, tracheobronchial tuberculosis, tuberculous pleurisy, mycoyin tuberculosis.
10. The use of a small molecule compound according to claim 1, wherein the small molecule compound KY1220 or a composition containing KY1220, wherein the small molecule compound KY1220 has a structural formula shown in I:
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