Shf analogue, pharmaceutical composition for preventing and / or treating tumors and application

Abstract

The invention provides a Shf analogue, a pharmaceutical composition for preventing and / or treating tumors and application, and belongs to the technical field of biological medicines. The amino acid sequence of the Shf analogue is at least one of SEQ ID NO: 1 to SEQ ID NO: 3. The invention designs a class of Shf analogues which have excellent STAT3 affinity, can be combined with highly expressed STAT3 in tumor cells, and promotes apoptosis of the tumor cells and inhibits proliferation and migration of the tumor cells by preventing STAT3 dimerization; meanwhile, the Shf analogue is almost non-toxic to normal cells and has excellent selectivity to tumors. Therefore, the Shf analogue and the pharmaceutically acceptable salt thereof can be potentially used in clinical treatment for preventing and / or treating tumors, and have wide development prospects.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to a class of Shf analogs, a pharmaceutical composition for preventing and / or treating tumors, and applications thereof. Background Art

[0002] Malignant tumors are one of the major diseases threatening human health and are the second leading cause of death in the world after cardiovascular diseases. Chemotherapy, as an important way to treat systemic tumors, has become the main means of tumor treatment. However, during the treatment process, the serious toxic side effects of chemotherapy drugs are a major drawback in their clinical use. At the same time, the development of tumor cell resistance to chemotherapy drugs is also one of the main reasons for chemotherapy failure. In recent years, with the development of tumor biology and related fields, molecular targeted drugs targeting key molecules in tumor signal transduction pathways have made breakthroughs, opening a new chapter in tumor chemotherapy.

[0003] Signal transducer and activator of transcription 3 (STAT3) is a key signal transduction protein involved in regulating cell growth, proliferation and apoptosis. It is widely expressed in a variety of cells and tissues and is closely related to tumorigenesis. In normal cells, the activation process of STAT3 is short-lived and controlled, while in most tumor cells, STAT3 is often abnormally activated continuously. Activated STAT3 forms STAT3-STAT3 dimers through its SH2 domain, regulating the expression of target genes such as anti-apoptotic protein Bcl-xL, proliferation-related protein c-Myc, pro-angiogenic factor VEGF, and invasion and metastasis-related protein MMP-2, thereby accelerating tumor development by inhibiting apoptosis, promoting cell proliferation, enhancing invasion and metastasis, and inducing inflammation and immunosuppression. Therefore, the development of tumor molecular targeted drugs targeting the STAT3 signaling pathway has important clinical value and broad application prospects.

[0004] SH2 domain connexin F (Shf) is a member of the SH2 connexin family. It can recognize specific phosphorylated Tyr residues of various signaling proteins and form protein complexes, activating downstream signaling pathways and regulating cell growth. Shf can act as a negative regulator of STAT3. It can competitively bind to STAT3 through the SH2 domain in its structure, inhibit the dimerization of STAT3, and effectively inhibit the proliferation and migration of tumor cells. However, different Shf analogs have significant differences in negatively regulating STAT3. Compounds that negatively regulate STAT3 are still in the preclinical research stage. The selection of Shf analogs with different structures is still a technical problem that needs to be solved urgently. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a class of Shf analogs, pharmaceutical compositions and uses for preventing and / or treating tumors. The Shf analogs have significant targeting affinity for STAT3 and can effectively prevent and / or treat tumors.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a class of Shf analogs, wherein the amino acid sequence of the Shf analog is at least one of SEQ ID NO: 1 to SEQ ID NO: 3.

[0008] Preferably, the hydroxyl group in the carboxyl group in the Arg structure at the C-terminus of the Shf analog is substituted by an amino group.

[0009] The present invention provides a pharmaceutical composition for preventing and / or treating tumors, wherein the pharmaceutical composition comprises the above-mentioned Shf analog or a pharmaceutically acceptable salt thereof.

[0010] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0011] The present invention also provides a use of the above Shf analog in the following a and / or b:

[0012] a. Preparation of products for the prevention and / or treatment of tumors;

[0013] b. Prepare products for inhibiting STAT3 protein.

[0014] Preferably, in the product for preventing and / or treating tumors, the tumor is a tumor that highly expresses STAT3.

[0015] Preferably, in the product for preventing and / or treating tumors, the tumor includes one or more of glioma, leukemia and liver cancer.

[0016] The present invention also provides a use of the above Shf analog in preparing a drug for targeted prevention and / or treatment of tumors.

[0017] Preferably, in the above-mentioned targeted drug for the prevention and / or treatment of tumors, the tumor is a tumor that highly expresses STAT3.

[0018] Preferably, in the above-mentioned targeted tumor prevention and / or treatment drug, the tumor includes one or more of glioma, leukemia and liver cancer.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The present invention provides a class of Shf analogs, pharmaceutical compositions and applications for preventing and / or treating tumors. The present invention designs a class of Shf analogs, which have excellent STAT3 affinity, can bind to STAT3 highly expressed in tumor cells, promote tumor cell apoptosis, and inhibit its proliferation and migration by preventing STAT3 dimerization; at the same time, Shf analogs are almost non-toxic to normal cells and have excellent selectivity for tumors. Therefore, the Shf analogs and pharmaceutically acceptable salts thereof can be potentially used in clinical treatments for preventing and / or treating tumors, and have broad development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The results of the effects of Shf analogs 1 to 3 prepared in Examples 1 to 3 on the in vivo tumor growth curve of U87; ** P ≤ 0.01 is the Student's t test result relative to the Saline group;

[0022] Figure 2 The results of the effects of Shf analogs 1 to 3 prepared in Examples 1 to 3 on the tumor weight in U87 cells after 14 days of treatment are shown in Table 1. ** P ≤ 0.01 is the Student's t test result relative to the Saline group. DETAILED DESCRIPTION

[0023] The present invention provides a class of Shf analogs, wherein the amino acid sequence of the Shf analog is at least one of SEQ ID NO: 1 to SEQ ID NO: 3.

[0024] At least one of the Shf analogs of the present invention as shown in SEQ ID NO: 1 to SEQ ID NO: 3 has significant targeting affinity for STAT3, thereby inhibiting STAT3 protein, which can not only significantly target tumors, but also inhibit their proliferation or migration, thereby achieving the effect of preventing and / or treating tumors, especially for tumors with high expression of STAT3.

[0025] As a preferred embodiment, the hydroxyl group in the carboxyl group in the Arg structure at the C-terminus of the Shf analog is replaced by an amino group, i.e., SEQ ID NO: 1-NH2, SEQ ID NO: 2-NH2, SEQ ID NO: 3-NH2, the amino acid sequence of SEQ ID NO: 1-NH2 is: FSSVPEIVHHYASRGLPIKGAEHMSLLYPVAIR-NH2, the amino acid sequence of SEQ ID NO: 2-NH2 is: PFSSVPEIVHHYASRKLPIGGAEHMSLLYPVAIR-NH2, the amino acid sequence of SEQ ID NO: 3-NH2 is: PFSSVPEIVHHYASRKLPIKGAEGMSLLYPVAIR-NH2. After the hydroxyl group in the carboxyl group in the Arg structure at the C-terminus of the Shf analog is replaced by an amino group, the stability of the Shf analogs shown in SEQ ID NO: 1 to SEQ ID NO: 3 is significantly improved.

[0026] The Shf analogues of the present invention not only retain the targeting affinity of Shf to STAT3, but also can significantly inhibit tumors, especially tumors with high expression of STAT3. The present invention optimizes the peptide sequence of Shf, which is conducive to subsequent large-scale industrial promotion.

[0027] The invention provides a method for preparing the Shf analogs. The method adopts a microwave-promoted Fmoc / tBu orthogonal protection solid phase synthesis strategy. The crude purity of the Shf analogs synthesized by microwave-promoted solid phase is high, and the crude purity is greater than 80%.

[0028] The present invention provides a pharmaceutical composition for preventing and / or treating tumors, wherein the pharmaceutical composition comprises the above-mentioned Shf analog or a pharmaceutically acceptable salt thereof.

[0029] In the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, wherein the excipient comprises an excipient, such as a solvent. In the medicine, the tumor comprises a tumor that highly expresses STAT3. Further preferably, the tumor comprises one or more of glioma, leukemia and liver cancer.

[0030] The present invention also provides a use of the above Shf analog in the following a and / or b:

[0031] a. Preparation of products for the prevention and / or treatment of tumors;

[0032] b. Prepare products for inhibiting STAT3 protein.

[0033] In the product for preventing and / or treating tumors, the tumor is a tumor that highly expresses STAT3. Further, the tumor includes one or more of glioma, leukemia and liver cancer. In the above applications, the Shf analog of the present invention can be used in combination with other anti-tumor products or products that inhibit STAT3 protein to achieve the purpose of preventing and / or treating tumors or inhibiting STAT3 protein activity, or the Shf analog can be used as the only active ingredient for preventing and / or treating tumors or inhibiting STAT3 protein activity. When used for preventing and / or treating tumors, the product can be administered orally or by injection.

[0034] The present invention also provides a use of the above Shf analog in preparing a drug for targeted prevention and / or treatment of tumors.

[0035] In the above-mentioned targeted tumor prevention and / or treatment drug, the tumor is a tumor that highly expresses STAT3. Further, the tumor includes one or more of glioma, leukemia and liver cancer. In the above-mentioned application, the Shf analog of the present invention can be used in combination with other targeted tumor prevention and / or treatment products or STAT3 protein inhibition products to achieve the purpose of tumor prevention and / or treatment, and the Shf analog can also be used as the only active ingredient for tumor prevention and / or treatment. When used for tumor prevention and / or treatment, the product can be administered orally or by injection.

[0036] In the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0037] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0038] In the present invention, the following abbreviations are used:

[0039] Et3N: triethylamine; NMM: N-methylmorpholine; DIEA: N,N'-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; Fmoc: N-9-fluorenylmethoxycarbonyl; DIC: N,N'-diisopropylcarbodiimide; CDI: N,N'-carbonyldiimidazole; DMAP: 4-dimethylaminopyridine; HOSU: N-hydroxysuccinimide; EDC.HCl: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester; HCTU: 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate; HOAT: 1-hydroxy-7-azobenzotriazole; HOBT: 1-hydroxy-benzotriazole; PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; HPLC: high performance liquid chromatography; ESI-MS: electrospray ionization mass spectrometry; Pal: palmitic acid; Gly: glycine; Ser: serine; Ala: alanine; Val: valine; Ile: isoleucine; Leu: leucine; Tyr: tyrosine; Phe: phenylalanine; His: histidine; Pro: proline; Met: methionine; Glu: glutamic acid; Lys: lysine; Arg: arginine.

[0040] Example 1

[0041] Microwave-enhanced solid phase synthesis of Phe-Ser-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Gly-Leu-Pro-Ile-Lys-Gly-Ala-Glu-His-Met-Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-NH2 (SEQ ID NO: 1-NH2, Shf analog 1)

[0042] (1) Swelling of resin

[0043] Weigh 50 mg of Fmoc-Rink amide-MBHAResin (substitution amount 0.4 mmol / g), swell it with 7 mL of DCM for 30 min, filter out DCM, swell it with 10 mL of NMP for 30 min, and finally rinse it with 7 mL of NMP, DCM and NMP respectively to obtain the swollen resin.

[0044] (2) Microwave-assisted removal of Fmoc protecting groups

[0045] Put the swollen resin into the reactor, add 7mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT, react in the microwave reactor for 1min, microwave power is 15W, reaction temperature is controlled within 50℃, use air compressor to cool, filter out the solution after the reaction is completed; add 7mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT in the microwave reactor for another 4min, microwave power is 25W, reaction temperature is controlled at 50℃, use air compressor to cool. After the reaction is completed, filter out the solution and wash with NMP. Obtain the resin with the Fmoc protecting group initially connected removed.

[0046] (3) Microwave-assisted synthesis of Fmoc-Arg(Pbf)-Rink amide-MBHAResin

[0047] Fmoc-Arg(Pbf)-OH (0.04 mmol), HBTU (0.04 mmol), HOBT (0.04 mmol) and DIPEA (0.08 mmol) were dissolved in 10 mL NMP, and the solution was added to the resin from which the Fmoc protecting group was removed. The reaction was carried out in a microwave reactor for 7 min, the microwave power was 25 W, the reaction temperature was controlled at 50 ° C, and the air was cooled by compressed air from an air compressor. After the reaction was completed, the reaction solution was filtered out, and the resin was washed 3 times with 7 mL of DCM and 7 mL of NMP.

[0048] (4) Detection of coupling efficiency

[0049] The coupling efficiency of the resin was qualitatively detected by the ninhydrin method or the bromophenol blue method. If the color reaction was negative, the next coupling cycle could be entered.

[0050] Ninhydrin method: Take a small amount of resin particles, wash them with ethanol, put them in a transparent vial, add 2 drops each of 5% ninhydrin ethanol, KCN pyridine solution (2mL 0.001M KCN ​​diluted in 98mL pyridine), and 80% phenol ethanol solution, heat at 100℃ for 5min. If the resin appears blue, it is positive.

[0051] Bromophenol blue method: Take a small amount of resin particles, wash them with dimethylacetamide, put them in a transparent vial, add 3 drops of 1% bromophenol blue dimethylacetamide solution, shake at room temperature for 3 minutes, if the resin appears blue, it is positive.

[0052] (5) Peptide chain extension

[0053] According to the sequence of the peptide chain of the compound, the deprotection and coupling steps of steps (2) to (4) are repeated from the C-terminus to the N-terminus to connect the corresponding amino acids, and the coupling microwave-promoted reaction time varies from 5 to 20 minutes to obtain a polypeptide-resin complex.

[0054] (6) Cleavage of peptides on resin

[0055] The obtained polypeptide-resin complex was placed in a reaction bottle, and 10 mL of the cleavage agent Reagent K (TFA / thioanisole / water / phenol / EDT, 82.5:5:5:5:2.5, V / V) was added to each reaction bottle. The mixture was shaken at 0°C for 30 min, and then reacted at room temperature for 3 h. After the reaction, the mixture was filtered, washed three times with a small amount of TFA and DCM, and the filtrate was combined. The filtrate was added to a large amount of ice ether to precipitate a white flocculent precipitate, and the crude product of the target polypeptide was obtained by refrigerated centrifugation.

[0056] (7) Peptide purification

[0057] The crude peptide was dissolved in 50% acetonitrile / water and purified by preparative liquid chromatography. The chromatographic conditions were: C18 reverse phase column (320mm×28mm, 5μm); mobile phase A: 0.1% TFA / water (V / V), mobile phase B: 0.1% TFA / acetonitrile (V / V); mobile phase gradient: 0-15min mobile phase B 40%-90%, 15-20min mobile phase B 90%; flow rate was 6mL / min and the detection wavelength was 214nm. The collected solution was lyophilized to obtain 30mg of pure product. The theoretical relative molecular mass of Shf analog 1 is 3772.38. ESI-MSm / z: calculate[M+4H] 4+ 944.10, [M+5H] 5+ 755.48; found [M+4H] 4+ 944.10, [M+5H] 5+ 755.47.

[0058] Example 2

[0059] Microwave-enhanced solid phase synthesis of Pro-Phe-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Lys-Leu-Pro-Ile-Gly-Gly-Ala-Glu-His-Met-Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-NH2 (SEQ ID NO: 2-NH2, Shf analog 2)

[0060] According to the general method described in Example 1, the Shf analog 2 of this example was synthesized according to the sequence shown in SEQ ID NO: 2-NH2, and the molecular weight was confirmed by ESI-MS.

[0061] The theoretical relative molecular mass of Pro-Phe-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Lys-Leu-Pro-Ile-Gly-Gly-Ala-Glu-His-Met-Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-NH2 (SEQ ID NO: 2-NH2) is 3772.38. ESI-MS m / z: calculate [M+4H] 4+ 944.10, [M+5H] 5+ 755.48; found[M+4H] 4+ 944.09, [M+5H] 5+ 755.47.

[0062] Example 3

[0063] Microwave-enhanced solid phase synthesis of Pro-Phe-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Lys-Leu-Pro-Ile-Lys-Gly-Ala-Glu-Gly-Met-Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-NH2 (SEQ ID NO: 3-NH2)

[0064] According to the general method described in Example 1, the Shf analog 3 of this example was synthesized according to the sequence shown in SEQ ID NO: 3-NH2, and the molecular weight was confirmed by ESI-MS.

[0065] The theoretical relative molecular mass of Pro-Phe-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Lys-Leu-Pro-Ile-Lys-Gly-Ala-Glu-Gly-Met-Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-NH2 (SEQ ID NO: 3-NH2) is 3763.41. ESI-MS m / z: calculate [M+4H] 4+ 941.85, [M+5H] 5+ 753.68; found [M+4H] 4+ 941.85, [M+5H] 5+ 753.68.

[0066] Example 4

[0067] (1) Detection of the targeting affinity of Shf analogs to STAT3

[0068] This example uses a static adsorption equilibrium experiment to determine the targeting affinity of Shf analog 1, Shf analog 2 and Shf analog 3 obtained in Examples 1 to 3 to STAT3:

[0069] The STAT3 protein content was determined by Kjeldahl method to be 7.55 mg / g wet gel, i.e., 85 nmol / g wet gel. The STAT3 protein was purchased from MCE, HY-P701098.

[0070] 0.1g wetgel, containing 8.5nmol STAT3 protein, was used, and 1mL of Shf analogs 1 to 3 obtained in Examples 1 to 3 respectively, and the control Scr peptide, containing different concentration gradients (initial concentrations: 2μM, 4μM, 6μM, 8μM, 10μM, 12μM, 14μM, 16μM, 18μM and 20μM) were respectively mixed in 20mM PBS solution, and slowly shaken at 4°C for 12h until static adsorption equilibrium was reached, and the supernatant was centrifuged at 3000rpm. The concentration of the small peptide in the supernatant was measured at a wavelength of 280nm using a NanoDrop 2000 ultra-micro spectrophotometer, and a blank agarose gel without coupling STAT3 protein was used as a blank control. Using the nonlinear fitting tool in Origin, the Langmuir isotherm adsorption equation was used for fitting, and the static adsorption maximum Qmax (nmol / g) and equilibrium dissociation constant Kd (μmol / L) of the example compound and the control Scr were obtained respectively. Among them, the Scr peptide is synthesized by disrupting the peptide sequence of the Shf analog.

[0071] Table 1 Static adsorption maximum and equilibrium dissociation constant of the example compounds and control Scr

[0072] Group Qmax(nmol / g) Kd(μmol / L) Scr small peptide 13.21±0.73 4.17±0.31 Shf analog 1 81.51±2.11 <![CDATA[0.06±0.03 ** ]]> Shf analog 2 82.85±2.35 <![CDATA[0.08±0.05 ** <!-- 5 -->]]> Shf analog 3 79.66±1.79 <![CDATA[0.11±0.03 ** ]]>

[0073] Note: **P≤0.01 is the Student's t test result relative to the Scr control group.

[0074] The results in Table 1 show that the maximum static adsorption Qmax of STAT3 protein immobilized at 85 nmol / g wet gel for Shf analog 1 reached 81.51±2.11 nmol / g wet gel, and the equilibrium dissociation constant Kd reached 0.06±0.03 μmol / L; the maximum static adsorption Qmax of Shf analog 2 reached 82.85±2.35 nmol / g wet gel; the equilibrium dissociation constant Kd reached 0.08±0.05 μmol / L; the maximum static adsorption Qmax of Shf analog 3 reached 79.66±1.79 nmol / g wet gel; the equilibrium dissociation constant Kd reached 0.11±0.03 μmol / L;

[0075] The maximum static adsorption value Qmax of the control Scr peptide reached 13.21±0.73nmol / g wet gel; the equilibrium dissociation constant Kd reached 4.17±0.31μmol / L. Shf analog 1, Shf analog 2 and Shf analog 3 were two orders of magnitude lower than the equilibrium dissociation constant Kd of the Scr peptide, showing significant targeting affinity; their maximum static adsorption value Qmax was basically consistent with the actual protein amount (85nmol / g wet gel) of STAT3 fixed on the CNBr-activated Sepharose 4B material, which was consistent with the 1:1 interaction model. This shows that Shf analog 1, Shf analog 2 and Shf analog 3 have good affinity for STAT3 protein.

[0076] (2) In vitro antitumor activities of Shf analog 1, Shf analog 2 and Shf analog 3 obtained in Examples 1 to 3, respectively

[0077] This example uses an in vitro cell proliferation assay to determine the in vitro antitumor activity of Shf analog 1, Shf analog 2, and Shf analog 3:

[0078] Human glioma cells U87, human leukemia cells K562, human liver cancer cells HepG-2, human gastric epithelial cells GES-1, and human umbilical vein endothelial cells HUVEC in good logarithmic growth phase were taken and 1×10 5 / mL density was inoculated in a 96-well culture plate and cultured for 24 hours, and then different concentration gradients (1.25μmol / L, 2.5μmol / L, 5μmol / L, 10μmol / L, 20μmol / L, 40μmol / L, 80μmol / L, 120μmol / L and 160μmol / L) of Shf analog 1, Shf analog 2 and Shf analog 3 were added and incubated for 48 hours. After the incubation, 20μL CCK-8 solution was added to each well, and the OD value at a wavelength of 450nm was detected by an enzyme reader after incubation for 2 hours. Finally, the IC of the test compound was calculated by GraphPadPrism 7.0. 50 value.

[0079] Table 2 In vitro cytotoxicity of Shf analogs 1 to 3 (μmol / L)

[0080] Grouping U87 K562 HepG-2 GES-1 HUVEC Shf analog 1 8.6±2.3 7.6±1.8 10.7±1.4 72.3±7.4 67.6±5.9 Shf analog 2 5.9±0.2 6.6±0.5 5.6±0.2 73.7±4.5 61.6±4.4 Shf analog 3 7.6±1.4 7.7±1.2 7.4±0.7 64.2±5.6 69.4±4.5

[0081] The results in Table 2 show that, compared with normal cells GES-1 and HUVEC, the Example compounds have significant cytotoxicity to tumor cells U87, K562 and HepG-2 with high expression of STAT3, indicating that the Example compounds have good broad-spectrum anti-tumor activity, but are less toxic to normal cells and have good selectivity for tumors with high expression of STAT3.

[0082] (3) In vivo antitumor activity of Shf analog 1, Shf analog 2 and Shf analog 3 obtained in Examples 1 to 3

[0083] This example uses a nude mouse tumor-bearing experiment to determine the in vitro antitumor activity of the example compounds:

[0084] Human brain glioma U87 cells were inoculated into the right axilla of balb / c nude mice and the tumors were grown to 100 mm. 3 The animals were then randomly divided into groups, with 6 animals in each group, and divided into a blank control group (denoted as Saline) and a drug-treated group, where the drug-treated groups were divided into Shf analog 1 group (denoted as SEQ.ID NO: 1), Shf analog 2 group (denoted as SEQ.ID NO: 2) and Shf analog 3 group (denoted as SEQ.ID NO: 3). The drug was administered intratumorally once every 2 days. The drug-treated groups were intravenously injected with 15 μg / mouse / time Shf analogs 1 to 3, and the blank control group was intravenously injected with an equal volume of normal saline. After drug administration, the body weight and tumor volume of the mice were measured daily to dynamically observe the anti-tumor effect of the compound. After 14 days of drug administration, the mice were killed, the tumor mass was surgically removed and weighed, and the relative tumor volume V (mm 3 ).

[0085] Figure 1 and Figure 2The results showed that Shf analog 1, Shf analog 2 and Shf analog 3 could effectively inhibit the growth of glioma in vivo and had good in vivo anti-tumor activity.

[0086] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A class of Shf analogs, characterized in that: The amino acid sequence of the Shf analog is at least one of SEQ ID NO: 1 to SEQ ID NO:

3.

2. The Shf analogue according to claim 1, characterized in that The hydroxyl group in the carboxyl group in the Arg structure at the C-terminus of the Shf analog is substituted with an amino group.

3. A pharmaceutical composition for preventing and / or treating tumors, characterized in that: The pharmaceutical composition comprises the Shf analogue or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition also includes pharmaceutically acceptable excipients.

5. Use of the Shf analogue according to claim 1 or 2 in the following a and / or b: a. Preparation of products for the prevention and / or treatment of tumors; b. Prepare products for inhibiting STAT3 protein.

6. The use according to claim 5, characterized in that: The tumor is a tumor that highly expresses STAT3.

7. The use according to claim 5, characterized in that: The tumor includes one or more of glioma, leukemia and liver cancer.

8. Use of the Shf analogue according to claim 1 or 2 in the preparation of targeted tumor prevention and / or treatment drugs.

9. The use according to claim 8, characterized in that: The tumor is a tumor that highly expresses STAT3.

10. The use according to claim 8, characterized in that: The tumor includes one or more of glioma, leukemia and liver cancer.

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