Benzothiazole compound and application thereof

Abstract

The invention discloses a benzothiazole compound and application of the benzothiazole compound. A series of benzothiazole compounds having inhibition effects on ISG20 and AML tumor cells are screened and verified, the structural formula is as follows: # imgabs0 #, and the representative compound LY0526 can reduce the expression of ISG20, and can also effectively kill AML cells and inhibit cell proliferation. LY0526 is simple in structure, relatively low in cost, mature in application and suitable for process production, so that the contribution of the invention to the technology in the field lies in providing the LY0526 and the structural analogue thereof as an ISG20 inhibitor for treating t (8; and 21) application of the AML.

Description

Technical Field

[0001] The invention belongs to the technical field of tumor drugs, relates to drugs for inhibiting acute myeloid leukemia, and specifically relates to a class of benzothiazole compounds and applications thereof. Background Art

[0002] Acute myeloid leukemia (AML) is one of the most malignant hematopoietic diseases, accounting for 80% of acute leukemia in adults, and is characterized by the uncontrolled expansion of immature myeloid cells. Although the remission rate of AML patients after initial chemotherapy has improved with the development of medical technology, 20-70% of patients still relapse after achieving complete remission (CR), resulting in a five-year survival rate of less than 30% for AML patients. About half of AML patients are accompanied by non-random chromosomal translocations, including balanced translocations and abnormal chromosome numbers. The four most common translocations are 11q23 / mixed lineage leukemia (MLL)-fusion protein, t(15;17) / PML-RAR, Inv(16) / core binding factor (CBF)b-MYH11, and t(8;21) / RUNX1-RUNX1T1. The key molecular changes caused by these molecular events can promote tumor cell proliferation and anti-apoptosis, resulting in AML transformation. In addition, although only 2% of newly diagnosed AML patients have extramedullary disease, up to 20% of AML patients experience extramedullary relapse after hematopoietic stem cell transplantation. Extramedullary metastasis of AML is mainly associated with the cytogenetic and molecular characteristics of leukemia and is associated with a poor prognosis.

[0003] The tumor microenvironment (TME) plays a key role in the occurrence, development, proliferation and survival of AML cells. In the bone marrow and peripheral blood, the phenotype and function of various immune cells in the TME are changed, which inhibits the anti-tumor immune response and enables tumor cells to escape immune surveillance. AML immunotherapy, such as bispecific T cell binding antibodies, chimeric antigen receptor T cells or natural killer cell therapy, or checkpoint inhibitors, is underway. Immunotherapy is conducive to the elimination of minimal residual lesions (MRD) of AML in order to achieve the deepest remission and prolong survival. At present, there are several clinical T cell immunotherapy targets for AML, including CD33, CD123, CLL-1, and CD70, but these targets have considerable challenges, such as unstable expression and high toxicity. Therefore, based on the unmet needs in the above AML treatment, identifying and developing AML-related tumor markers that can affect AML proliferation, overcome extramedullary metastasis, and improve the function of immune cells in the TME, and developing corresponding targeted small molecule inhibitors, will help improve the efficacy of AML, restore patients' anti-tumor immunity, and ultimately prolong patient survival.

[0004] Interferon-stimulated exonuclease gene 20 (ISG20) is an interferon-stimulated protein located on human chromosome 15q26. It is also known as estrogen-regulated transcription 45 protein and is an RNA exonuclease induced by interferon (IFN type I and II) or double-stranded RNA. ISG20 can cut single-stranded RNA or DNA and is closely related to the host's antiviral innate immune defense. Multiple studies have shown that ISG20 is highly expressed in a variety of solid tumors and is involved in the occurrence and progression of tumors: for example, ISG20 is upregulated in cervical cancer and renal clear cell carcinoma; in gliomas, high expression of ISG20 indicates poor overall survival of patients; increased expression has also been reported in hematological tumors such as diffuse large B-cell lymphoma and leukemia, but no further mechanism has been explored. The specific mechanism of how ISG20 affects the prognosis of cancer patients is still under exploration. Studies have found that ISG20 promotes the proliferation and metastasis of renal clear cell carcinoma by regulating the expression of CCND1 / MMP9. ISG20, which has exonuclease activity, enhances angiogenesis through the regulation of thyroid hormone and supports the progression of hepatocellular carcinoma (HCC). In addition to its effects on tumor proliferation and metastasis, in terms of the immune microenvironment, studies in human gliomas have found that high expression of ISG20 is associated with increased infiltration of monocyte-derived macrophages and neutrophils and inhibition of adaptive immune responses (Gao Mengqi et al., ISG20 promotes local tumor immunity and contributes to poor survival in human glioma, Oncoimmunology, 8(2): e1534038, 2019). The expression of ISG20 is also positively correlated with the expression of immune checkpoints and inhibitory receptors (PD-1, PD-L1, and CTLA4), and may be involved in the inhibition of immune cell function. Combined with the effects of ISG20 molecules on tumor cells and the immune microenvironment, it is speculated that it can be explored as a potential therapeutic target in AML.

[0005] Traditional drug discovery and development is very time-consuming, labor-intensive, and costly. Protein structure-based screening (SBVS) is an applied computer simulation technology that uses the three-dimensional (3D) structure of the biological target obtained from X-rays, NMR, or computational modeling to dock compounds with diverse spatial conformations to binding sites, and select a subset of these compounds based on the predicted binding scores for further biological evaluation, thereby discovering small molecule compounds that have the potential to regulate protein function. Combined with the computing power of supercomputers, SBVS technology can screen a million-level compound library in a short period of time, saving a lot of manpower, time, and drug development funds. At present, the human ISG20 protein has been successfully resolved (PDB ID: 1WLJ), with a resolution of up to 1.31 million bp. (Tatsuya Horio, et al. Crystal structure of human ISG20, an interferon-induced antiviral ribonuclease, FEBS Letters, 577, 1-2, 111-116, 2004), which can meet the needs of virtual screening for protein structure. Based on this, a small molecule compound that specifically inhibits ISG20 expression and inhibits the growth of t(8;21) AML cells can be found to achieve targeted treatment of t(8;21) AML. Summary of the invention

[0006] The present invention is based on the above research and provides a class of benzothiazole compounds having an inhibitory effect on t(8;21)AML through screening.

[0007] The technical route of the present invention is as follows: Clinical studies have found that high expression of the interferon-stimulated gene ISG20 is significantly associated with patient relapse and poor prognosis. Knocking down ISG20 can induce AML cell apoptosis and significantly inhibit its proliferation by regulating the cell cycle and TNF-α signaling pathway. Based on this study, a high-throughput virtual screening based on the ISG20 protein structure was carried out to select 19 compounds with specific results, and then cells were used for phenotypic screening, among which the positive compound LY0526 had good inhibitory activity. The binding of the positive compound LY0526 to the target protein was further analyzed, and a second round of cell screening was continued with 12 structural analogs to find a series of small molecule drugs that inhibit ISG20, which will help treat t(8;21)AML leukemia.

[0008] The first object of the present invention is to provide a benzothiazole compound, and another object is to provide the use of the benzothiazole compound in the preparation of AML therapeutic drugs.

[0009] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] In the first aspect of the present invention, a benzothiazole compound is provided, the structure of which is shown in the following formula I:

[0011]

[0012] Wherein, R1 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

[0013] n is 1, 2 or 3;

[0014] R2, R3 are substitutions at the ortho, meta or para positions on the benzene ring A;

[0015] R2 and R3 are each selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, cyano and methoxy.

[0016] Preferably, the code and chemical name of the benzothiazole compounds of the present invention are as follows:

[0017] LY0526: 2-phenyl-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)ethane-1-sulfonamide;

[0018] LY0514: 1-(3-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0019] LY0504: 1-(4-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0020] LY0411: N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0021] LY0521: 1-(3,4-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0022] LY0417: 4-(tert-Butyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0023] LY0519: 1-(2-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0024] LY0525: 1-(3-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0025] LY0392: 4-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0026] LY0523: 1-(2,5-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0027] LY0506: 1-(2-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0028] LY0528: 3-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0029] LY0409: 4-methoxy-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide.

[0030] Most preferably, compound LY0526 and its structural analogs LY0514, LY0411, LY0417, LY0519, LY0525, LY0523, LY0506, LY0409.

[0031] The results of biomembrane interference technology (BLI) showed that LY0526 interacted with ISG20, which indicated that this series of compounds could specifically bind to ISG20 to exert an inhibitory effect. Subsequent tests of its structural analogs LY0514, LY0411, LY0417, LY0519, LY0525, LY0523, LY0506, and LY0409 also showed good inhibitory effects. In addition, the results of leukemia cell experiments showed that the IC of LY0526 in Kasumi-1 cells was 50 At a concentration of 46.7 μM, the IC 50 The IC of THP-1 is 23.93 μM. 50 The IC value of HEL is 36.38 μM. 50 It is 26.73 μM, indicating that the small molecule inhibitor LY0526 has a certain inhibitory ability on the proliferation of AML leukemia cells.

[0032] The second aspect of the present invention provides the use of the above-mentioned benzothiazole compound, specifically the use in preparing AML therapeutic drugs or in preparing ISG20 inhibitors. Since the benzothiazole compound has the effect of inhibiting ISG20, it is further preferably used in preparing t(8;21) type AML therapeutic drugs whose target gene is ISG20.

[0033] The third aspect of the present invention provides a pharmaceutical composition for treating AML, comprising an active ingredient and pharmaceutically / immunologically acceptable excipients, wherein the active ingredient comprises the benzothiazole compound described above, preferably the above-mentioned LY0526 and its structural analogs.

[0034] Preferably, the pharmaceutical composition is a pharmaceutical composition for treating t(8;21) type AML.

[0035] Preferably, the pharmaceutical composition is an acquired drug resistance inhibitor and can be used in combination with other anti-tumor active ingredients. Tumor treatment includes but is not limited to: radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.

[0036] That is, the present invention provides an acquired drug resistance inhibition product, which comprises:

[0037] (A) Inhibitors of ISG20;

[0038] (B) a pharmaceutically or immunologically acceptable carrier or excipient;

[0039] (C) optionally, one or more other anti-AML active ingredients.

[0040] The term "pharmaceutically / immunologically acceptable" ingredients are substances that are suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., have a reasonable benefit / risk ratio. As used herein, the term "effective amount" refers to an amount that can produce a function or activity in humans and / or animals and can be accepted by humans and / or animals.

[0041] The term "pharmaceutically acceptable carrier" refers to a carrier for administering a therapeutic agent, including various excipients and diluents. The term refers to pharmaceutical carriers that are not themselves essential active ingredients and are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A full discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ 1991).

[0042] The pharmaceutically acceptable carrier in the composition may contain a liquid such as water, saline, glycerol and ethanol. In addition, auxiliary substances such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting agents or emulsifiers, flavoring agents, pH buffer substances, etc. may also be present in these carriers. Generally, these substances can be formulated in a non-toxic, inert and pharmaceutically acceptable aqueous carrier medium, wherein the pH is generally about 5-8, preferably, the pH is about 6-8.

[0043] The active substance in the composition of this invention accounts for 0.001-99.9wt% of the total weight of the composition; preferably 1-95wt% of the total weight of the composition, more preferably 5-90wt%, more preferably 10-80wt%, and the remainder is pharmaceutically acceptable carriers and other additives.

[0044] In terms of pharmaceutical form, the composition of the present invention may be in solid form (such as granules, tablets, lyophilized powders, suppositories, capsules, sublingual tablets) or liquid form (such as oral solutions, injection preparations) or other suitable forms.

[0045] The composition of the present invention is a unit dosage form or a multiple dosage form. "Unit dosage form" refers to a dosage form in which the product is prepared into a single dosage form for the convenience of administration, including but not limited to various solid doses (such as tablets), liquids, capsules, and sustained-release agents. In some embodiments herein, the composition herein is administered at an appropriate frequency, such as daily, every other day, weekly, every other week or two weeks, monthly, every other month or two months, for example, 1 to 6 doses are administered.

[0046] It should be understood that the effective dose of the active substance used may vary with the severity of the subject to be administered or treated. The specific situation is determined according to the individual situation of the subject (e.g., the subject's weight, age, physical condition, the desired effect), which is within the scope of the skilled physician's judgment.

[0047] The fourth aspect of the present invention provides an ISG20 inhibitor, comprising an active component and a pharmaceutically / immunologically acceptable excipient, wherein the active component also includes the benzothiazole compound described above, and the above-mentioned LY0526 and its structural analogs are also preferred.

[0048] Beneficial technical effects of the present invention:

[0049] The present invention screened and verified a series of benzothiazole compounds that have inhibitory effects on ISG20 and AML tumor cells, among which the representative compound LY0526 can not only reduce the expression of ISG20, but also effectively kill AML cells and inhibit cell proliferation. LY0526 has a simple structure, relatively low cost and mature application, and is suitable for process production. Therefore, the contribution of the present invention to the art is to provide the application of LY0526 and its structural analogs as ISG20 inhibitors in the treatment of t(8;21)AML, which is also the significance of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 It was shown that ISG20 was highly expressed in AML patient cells and was significantly correlated with poor patient prognosis.

[0051] Figure 2 It was shown that ISG20 knockdown resulted in blocked proliferation and increased apoptosis of AML cells.

[0052] Figure 3 The molecular docking results of the positive compound LY0526 and the target protein ISG20 are shown;

[0053] Figure 4The structures and hydrogen spectrum information of compound LY0526 and its analogs are shown: A, LY0526 (2-phenyl-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)ethane-1-sulfonamide); B, LY0514 (1-(3-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide); C, LY0504 (1-(4-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)ethanesulfonamide). -6-yl) methanesulfonamide); D, LY0411 (N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide); E, LY0521 (1-(3,4-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide); F, LY0417 (4-(tert-butyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide); G, LY0519 (1- LY0525 (1-(3-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide); I, LY0392 (4-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide); J, LY0523 (1-(2,5-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide); LY0506 (1-(2-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide); L, LY0528 (3-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide); M, LY0409 (4-methoxy-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide).

[0054] Figure 5 The ISG20 small molecule inhibitor screening process and results are shown.

[0055] Figure 6 The IC50 test results of LY0526 in multiple AML cell lines (Kasumi-1, AE9a, THP-1, HEL) are shown. DETAILED DESCRIPTION

[0056] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

[0057] Example 1 ISG20 expression is significantly correlated with recurrence and prognosis of t(8;21) AML

[0058] By analyzing the CD34 + The data of overexpression of RUNX1::RUNX1T1 in HSC cells and knockdown of RUNX1::RUNX1T1 in kasumi-1 cells showed that the expression level of ISG20 was significantly increased when RUNX1::RUNX1T1 was overexpressed, and the expression level of ISG20 was significantly decreased after knockdown of RUNX1::RUNX1T1, indicating that ISG20 is a target gene of RUNX1::RUNX1T1 ( Figure 1 A and 1B). In addition, GEPIA database analysis revealed that the expression of ISG20 in t(8;21) AML patient cells was significantly higher than that in normal subjects ( Figure 1 C and 1D), and high expression is associated with poor prognosis ( Figure 1 E and 1F), which indicates that it is feasible to treat AML by screening ISG20 small molecule inhibitors. In addition, 42 samples of newly diagnosed AML patients, 7 samples of relapsed AML and 24 normal human bone marrow mononuclear cells were collected for RNA-seq sequencing, and it was found that the expression of ISG20 in AML patients was slightly increased compared with normal controls, while the expression of ISG20 in relapsed AML patients was significantly higher than that in normal controls ( Figure 1 G).

[0059] Example 2 Knockdown of ISG20 induces apoptosis of AML cells and significantly inhibits cell proliferation

[0060] In order to clarify the role of ISG20 in t(8;21) leukemia, t(8;21) AML cells were infected with ISG20 shRNA plasmid-packaged virus to study the effect of ISG20 knockdown on cell growth and proliferation in Kasumi-1 cells. Since the shRNA plasmid expresses a puromycin reporter gene downstream of the ISG20 short hairpin sequence as a marker, we selected puromycin to screen positive LSC cells 48 hours after infection with the ISG20 shRNA virus. The results showed that compared with the control group, the expression of ISG20 mRNA and protein levels in Kaumi-1 cells in the ISG20 shRNA knockdown group was significantly reduced, indicating that the ISG20 knockdown cell model constructed with shRNA has been successfully constructed (2A). CCK8 experiments showed that the proliferation efficiency of Kaumi-1 cells was significantly decreased after 48 hours of puromycin selection ( Figure 2 B). At the same time, flow cytometry analysis of apoptosis experiments showed that compared with the control group, the early apoptotic cells of Kaumi-1 cells in the ISG20 knockdown group (Annexin-V + PI - ) significantly increased ( Figure 2 D and 2E), late apoptosis (Annexin-V + PI +) also increased significantly ( Figure 2 D and 2F).

[0061] Example 3 High-throughput virtual screening based on ISG20 protein structure

[0062] The high-resolution crystal structure of ISG20 protein (PDB ID 1WLJ) was downloaded from the protein structure database PDB, and the protein was preprocessed using the Schrödinger protein preparation module, and the ISG20 protein binding pocket was obtained using the Schrödinger software Sitemap module. The 1.3 million compound library of ChemDiv was preprocessed using Schrödinger's ligand preparation module, and the gridding file of the binding pocket was generated using the Schrödinger software gridding module. The molecular docking module was used to perform high-throughput virtual screening of the compound library using the HTVS mode. The top 10% of the compounds were docked and screened in the SP mode, and then the top 10% of the compounds were docked and screened in the XP mode. Finally, the top 10% of the compounds were clustered for compound structure, and selected by naked eye to select 19 compounds with specific results.

[0063] The cells were used for phenotypic screening, and the positive compound LY0526 showed good inhibitory activity. The binding of the positive compound LY0526 to the target protein was analyzed, and the results were as follows: Figure 3 As shown, the compound LY0526 can fit well into the binding pocket of the ISG20 protein. Then the second round of cell screening was continued, and 12 structural analogs of LY0526 were screened. The chemical names of LY0526 and its structural analogs are as follows:

[0064] LY0526: 2-phenyl-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)ethane-1-sulfonamide;

[0065] LY0514: 1-(3-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0066] LY0504: 1-(4-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0067] LY0411: N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0068] LY0521: 1-(3,4-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0069] LY0417: 4-(tert-Butyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0070] LY0519: 1-(2-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0071] LY0525: 1-(3-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0072] LY0392: 4-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0073] LY0523: 1-(2,5-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0074] LY0506: 1-(2-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide;

[0075] LY0528: 3-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide;

[0076] LY0409: 4-methoxy-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide.

[0077] The structure and proton spectrum information of compound LY0526 and its analogs are as follows Figure 4 Wherein, the compound LY0526 and its analogs were purchased from ChemDive, with a purity greater than 95%, the hydrogen spectrum was obtained by 400 Hz Bruker NMR test, and the solvent was deuterated DMSO.

[0078] Example 4 Screening of ISG20 small molecule inhibitors

[0079] Kasumi-1 and HEL cells were evenly plated on a 384-well plate, with 2000-3000 cells per well. Drugs were added to a final concentration of 50 μM. The cells were cultured at 37°C and 5% CO2 for 48 hours. Luminescent Cell Viability high-sensitivity bioluminescence detection technology was used to detect the inhibitory effect of small molecule inhibitors on Kasumi-1 cells, and the small molecule compounds LY0526, LY0633 and LY0481 had good inhibitory efficiency on cells ( Figure 5 A). We then purified the ISG20 protein in vitro and used biomembrane interference technology (BLI) to verify whether these three small molecules interacted with ISG20 in vitro. The results showed that LY0526 interacted with ISG20 ( Figure 5 BD), it is inferred that this series of compounds can specifically bind to ISG20 to exert an inhibitory effect. Subsequent tests of its structural analogs LY0514, LY0411, LY0417, LY0519, LY0525, LY0523, LY0506, and LY0409 also showed good inhibitory effects ( Figure 5 E and 5F).

[0080] Example 5 Effects of ISG20 small molecule inhibitors in AML cells

[0081] In order to further verify the effect of the small molecule inhibitor LY0526 on AML cells, Kasumi-1 cell line and AE9a cell line representing t(8;21)AML, as well as human monocytic leukemia cell line (THP1) and erythrocytic leukemia cell line (HEL) were selected to verify the anti-tumor cell effect of the small molecule inhibitor. Figure 6 The IC of LY0526 in Kasumi-1 cells was shown. 50 The concentration is 46.7 μM ( Figure 6 A) IC of AE9a 50 23.93μM( Figure 6 B), IC of THP-1 50 36.38μM( Figure 6 C) HEL IC 50 26.73μM( Figure 6 D), which confirms that small molecule inhibitors have a certain ability to inhibit the proliferation of AML leukemia cells.

[0082] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. The use of benzothiazole compounds in the preparation of drugs for treating acute myeloid leukemia, characterized in that: The structure of the benzothiazole compound is shown in the following formula I: Wherein, R1 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl; n is 1, 2 or 3; R2, R3 are substitutions at the ortho, meta or para positions on the benzene ring A; R2 and R3 are each selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, cyano and methoxy.

2. The use according to claim 1, characterized in that: in, The acute myeloid leukemia is selected from t(8;21) type AML.

3. The use according to claim 1, characterized in that: The benzothiazole compound is selected from any of the following compounds or combinations of compounds: LY0526: 2-phenyl-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)ethane-1-sulfonamide; LY0514: 1-(3-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0504: 1-(4-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0411: N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0521: 1-(3,4-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0417: 4-(tert-Butyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0519: 1-(2-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0525: 1-(3-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0392: 4-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0523: 1-(2,5-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0506: 1-(2-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0528: 3-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0409: 4-methoxy-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide.

4. Use of benzothiazole compounds in the preparation of ISG20 inhibitors, characterized in that: The structure of the benzothiazole compound is shown in the following formula I: Wherein, R1 is methyl, ethyl, n-propyl, isopropyl or cyclopropyl; n is 1, 2 or 3; R2, R3 are substitutions at the ortho, meta or para positions on the benzene ring A; R2 and R3 are each selected from any one of hydrogen, fluorine, chlorine, bromine, methyl, cyano and methoxy.

5. The use according to claim 1, characterized in that: in, The AML is selected from t(8;21) type AML.

6. The use according to claim 1, characterized in that: The benzothiazole compound is selected from any of the following compounds or combinations of compounds: LY0526: 2-phenyl-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)ethane-1-sulfonamide; LY0514: 1-(3-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0504: 1-(4-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0411: N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0521: 1-(3,4-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0417: 4-(tert-Butyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0519: 1-(2-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0525: 1-(3-fluorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0392: 4-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0523: 1-(2,5-dimethylphenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0506: 1-(2-chlorophenyl)-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)methanesulfonamide; LY0528: 3-cyano-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide; LY0409: 4-methoxy-N-(2-(propylsulfonyl)benzo[d]thiazol-6-yl)benzenesulfonamide.

7. A pharmaceutical composition for treating acute myeloid leukemia, characterized in that: The invention comprises an active component and pharmaceutically or immunologically acceptable auxiliary materials, wherein the active component is selected from the benzothiazole compound according to any one of claims 1 to 3.

8. The pharmaceutical composition for treating acute myeloid leukemia according to claim 7, characterized in that: The medicine composition is a medicine for treating t(8;21) type AML.

9. The pharmaceutical composition for treating acute myeloid leukemia according to claim 7, characterized in that: The pharmaceutical composition is used in combination with other AML therapeutic drugs.

10. An ISG20 inhibitor, characterized in that The invention comprises an active component and pharmaceutically or immunologically acceptable auxiliary materials, wherein the active component is selected from the benzothiazole compound according to any one of claims 4 to 6.

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