WO2021223713A1 - Application d'un inhibiteur de sms2 dans la préparation d'un médicament pour le traitement du cancer du sein hautement invasif - Google Patents

Application d'un inhibiteur de sms2 dans la préparation d'un médicament pour le traitement du cancer du sein hautement invasif Download PDF

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WO2021223713A1
WO2021223713A1 PCT/CN2021/091931 CN2021091931W WO2021223713A1 WO 2021223713 A1 WO2021223713 A1 WO 2021223713A1 CN 2021091931 W CN2021091931 W CN 2021091931W WO 2021223713 A1 WO2021223713 A1 WO 2021223713A1
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sms2
breast cancer
macrophages
cells
compound
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Chinese (zh)
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董继斌
余科
邓燕
叶德泳
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石家庄以岭药业股份有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TNBC Triple-Negative Breast Cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 human epidermal Growth factor receptor
  • TNBC has a high degree of malignancy, common lung and brain metastases, and currently lacks targeted effective treatment.
  • the average survival time of patients is maintained at about 15 months. It is the most common subtype of breast cancer death (N Engl J Med 2009; 360:790-800 ).
  • SMS2 is abundantly expressed in macrophages and plays an important role in regulating inflammation; down-regulating the activity of SMS2 can alleviate the inflammatory state of peritoneal macrophages induced by LPS, while overexpression of SMS2 induces the expression of aortic inflammatory biomarker molecules ( Life Sci. 2012 Jun 6; 90(21-22):867-73).
  • SMS2 inhibitors can be used to prevent and treat atherosclerosis and inflammatory bowel disease (the application of Y9 in anti-atherosclerosis, CN107456453A; 4-(2,6-dichlorobenzyloxy)-3 -(3-Aminopyridine)benzo[d]isoxazole in the preparation of drugs for the prevention and treatment of inflammatory bowel disease, CN 111481548 A), but its impact on macrophages and tumor microenvironment and in the prevention and treatment of inflammatory bowel disease The effect in the treatment of human and animal triple-negative breast cancer has not been confirmed by experiments.
  • One of the objectives of the present invention is to provide new uses of SMS2 inhibitors.
  • the present invention discovers the important regulatory effect of SMS2 in tumor microenvironment M2 type macrophages (TAMs). SMS2 inhibitors are effective in treating triple negative breast cancer (TNBC) and have application development value.
  • TAMs tumor microenvironment M2 type macrophages
  • the present invention provides the application of the SMS2 inhibitor in the preparation of drugs for treating highly aggressive breast cancer.
  • the SMS2 inhibitor includes a compound represented by formula (I),
  • the SMS2 inhibitor includes a reagent material for depriving SMS2 activity, for example, a reagent material for knocking out the SMS2 gene.
  • the highly aggressive breast cancer is triple-negative breast cancer.
  • the SMS2 inhibitor can effectively inhibit the type 2 polarization of macrophages by reducing the activity of sphingomyelin synthase 2 and the level of sphingomyelin in the body, and by reducing M2 type macrophages in the tumor microenvironment of triple-negative breast cancer.
  • the degree of infiltration of cells and other bone marrow-derived immunosuppressive cells reshapes the tumor microenvironment, thereby inhibiting the in situ growth of triple-negative breast cancer and the formation and growth of lung metastases brought about by blood.
  • the drug is used to prevent and/or treat highly aggressive breast cancer through one or more of the following approaches:
  • the present invention also provides a drug for resisting highly invasive breast cancer, wherein the drug is a preparation prepared from an SMS2 inhibitor as an active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients.
  • the SMS2 inhibitor includes a compound represented by formula (I),
  • the route of administration of the drug is oral or intravenous injection.
  • the SMS2 inhibitor can effectively inhibit the type 2 polarization of macrophages by reducing the activity of sphingomyelin synthase 2 and the level of sphingomyelin in the body, and by reducing M2 type macrophages in the tumor microenvironment of triple-negative breast cancer.
  • the degree of infiltration of cells and other bone marrow-derived immunosuppressive cells reshapes the tumor microenvironment, thereby inhibiting the in situ growth of triple-negative breast cancer and the formation and growth of lung metastases brought about by blood.
  • the invention also provides the application of SMS2 as a target in screening drugs for the prevention and/or treatment of highly aggressive breast cancer.
  • the present invention proves that the SMS2 inhibitor has a structure as shown in formula (I), has the effect of inhibiting highly invasive breast cancer, and provides a new effective therapeutic drug for the treatment of highly invasive breast cancer.
  • Figures 4A-4B are the data analysis results of 522 breast cancer tumor samples in the TCGA database: Figure 4A shows that the high expression of SMS2 in breast cancer patients’ tumors is related to the high CD206/CD68 ratio; Figure 4B shows that in breast cancer patients’ tumors, SMS2 High expression is related to high expression of FOXP3, CD11b and CD33, ***, P ⁇ 0.001; ****, P ⁇ 0.0001.
  • Figures 5A-5B show the relationship between high SMS2 expression and patient prognosis:
  • Figure 5A shows the high expression of SMS2 in "basal-like" breast cancer;
  • Figure 5B shows that high SMS2 expression is related to low RFS in "basal-like” breast cancer , ***, P ⁇ 0.001.
  • Figure 7 shows that the lack of SMS2 activity has no effect on the type 1 polarization of macrophages under IL-4 induced conditions.
  • Figures 8A-8B show that compound I significantly reduces the expression of M2 type surface protein in BMDM cells induced by IL-4:
  • Figure 8A shows the percentage of F4/80+CD206+ cells in BMDM cells detected by flow cytometry and the results of CD206MFI;
  • Figure 8B It is the result of CD206 MFI of RAW 264.7 cells detected by flow cytometry, **, P ⁇ 0.01; ***, P ⁇ 0.001.
  • Figures 9A-9B show that compound I significantly reduced the protein expression of CD206 and Arg1 in BMDM and RAW264.7 cells induced by IL-4:
  • Figure 9A is the result of Western Blot detection of the protein expression of Arg1 and CD206 in BMDM cells;
  • Figure 9B is the Western Blot Detect the protein expression results of Arg1 and CD206 in RAW 264.7 cells; **, P ⁇ 0.01; ***, P ⁇ 0.001.
  • Figures 11A-11B show that compound I significantly reduces the expression of M2 type surface protein in BMDM cells induced by TNBC cell conditioned medium, but has no effect on M1 type:
  • Figure 11A shows that compound I significantly reduces the cell surface of BMDMs induced by 4T1 cell conditioned medium The expression of CD206 has no obvious inhibitory effect on the expression of CD86;
  • Figure 11B shows that compound I significantly reduces the expression of CD206 on the cell surface of BMDMs induced by MDA-MB-231 cell conditioned medium, but has no obvious inhibitory effect on the expression of CD86; **, P ⁇ 0.01.
  • Figures 12A-12B show that Compound I significantly reduces the secretion of IL-10 and TGF- ⁇ in BMDM cells induced by TNBC cell conditioned medium:
  • Figure 12A is the result of 4T1-CM inducing the secretion of IL-10 and TGF- ⁇ in BMDM cells;
  • 12B is the result of MDA-MB-231-CM induced BMDM cells to secrete IL-10 and TGF- ⁇ ; **, P ⁇ 0.01; ***, P ⁇ 0.001; ****, P ⁇ 0.0001.
  • Figures 14A-14B show that compound I reduces the migration ability of 4T1 cells induced by M2 type macrophages:
  • Figure 14A is a schematic diagram of macrophage conditioned medium collection;
  • Figure 14B is the results of 4T1 cell migration experiments; ***, P ⁇ 0.001 .
  • Figure 15 shows that Compound I reduces the total SM level in mouse plasma; ***, P ⁇ 0.001.
  • Figures 17A-17B show that compound I effectively reduces the number of M2 macrophages infiltrated in TNBC lung metastases, but has no effect on the polarization state of macrophages under normal physiological conditions:
  • Figure 17A shows that compound I affects mice in normal physiological conditions Peritoneal macrophage polarization has no obvious inhibitory effect;
  • Figures 19A to 19C show that Compound I can effectively reduce the in situ growth of triple-negative breast cancer in mouse models, and effectively promote the necrosis and apoptosis of tumor tissue in situ:
  • Figure 19A shows that the weight of the tumor in the compound I administration group was significantly reduced
  • Figure 19B shows that the tumor necrosis and apoptosis of the compound I administration group increased significantly
  • Figures 20A-20B show that Compound I effectively increases effector T cells in the tumor microenvironment and reduces immunosuppressive M2 type macrophages:
  • Figure 20A shows that Compound I effectively increases CD8+ T cells infiltrating the tumor stroma;
  • SMS2 in this context refers to sphingomyelin synthase 2.
  • the compound I of the present invention is the compound represented by the aforementioned formula (I).
  • the present invention uses Oncomine and TCGA online database analysis to find that SMS2 has abnormal expression in human triple-negative breast cancer.
  • the high expression of SMS2 is related to the high infiltration of M2 type macrophages and is related to the prognosis of tumor patients. Relatively worse.
  • the present invention firstly uses primary bone marrow macrophages of SMS2 gene knockout mice to verify that SMS2 activity is missing, which can significantly reduce IL4-induced macrophage type 2 polarization, which lays the experimental foundation for the present invention.
  • the present invention selects the most representative triple-negative breast cancer (TNBC) cell lines 4T1 and MDA-MB-231 from humans and mice to target bone marrow primary macrophages (BMDM) derived from BALBC mice (BMDM in the subsequent examples). All have the same meaning) to carry out in vitro experiments; use the mouse triple-negative breast cancer in situ and lung blood metastasis models established by 4T1 to carry out in vivo experiments.
  • TNBC triple-negative breast cancer
  • BMDM bone marrow primary macrophages
  • SMS2 can be used as a drug target for the treatment of highly aggressive breast cancer represented by TNBC.
  • Compound I can be used to prevent and treat triple-negative breast cancer in humans and animals.
  • Example 1 The experimental dose of Compound I is effective and safe.
  • the 3-fold inhibition rate (IC 50 ) Concentration is used as the experimental dose of the present invention, this dose has a significant SMS2 activity inhibitory effect on the same experimental cells (as shown in Figure 1), and the cytotoxic effect at this dose is negligible (as shown in Figure 2), so The dosage of the compound selected in the present invention is safe and effective.
  • SMS2 is highly expressed in patients with basal-like breast cancer, and is positively correlated with the high infiltration of immunosuppressive cells such as M2 macrophages in cancer tissues and the poor prognosis of the patients.
  • the Oncomine database https://www.oncomine.org was used to compare and analyze the differences in the expression of SMS2 in breast cancer tissues and normal breast tissues; it was found that SMS2 was more aggressive than normal breast tissues.
  • the expression in breast cancer is significantly increased (as shown in Figure 3).
  • TCGA database Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumors. Nature 2012; 490: 61-70.
  • SMS2 In the samples with high SMS2 gene expression, the ratio of CD206/CD68 is higher, indicating that the high expression of SMS2 is related to the high degree of M2 macrophage infiltration. Similarly, the higher the expression of FOXP3, CD11b and CD33 in the samples with high SMS2 gene expression, indicating that the high expression of SMS2 is related to the high infiltration of regulatory T cells and suppressor cells derived from bone marrow.
  • SMS2-H breast cancer patients
  • the high expression of SMS2 in tumors (SMS2-H) is related to the high ratio of CD206/CD68
  • the high expression of SMS2 in tumors of breast cancer patients is related to the high expression of FOXP3, CD11b and CD33.
  • SMS2-L in the figure represents the low expression of SMS2. ***, P ⁇ 0.001; ****, P ⁇ 0.0001.
  • the mRNA expression of 522 breast cancer samples in the TCGA database was calculated according to the following formula: (KRT5+KRT14)/(KRT8+KRT18). According to the median of the sample, breast cancer is divided into two types: Basal-like and Luminal-like. Above the median, it is defined as “basal-like” breast cancer; The number of digits is defined as “duct-like” breast cancer.
  • FIG. 5A shows the relationship between high SMS2 expression and patient prognosis.
  • Figure 5A shows the high expression of SMS2 in "basal-like” breast cancer;
  • Figure 5B shows the high expression of SMS2 in "basal-like” breast cancer.
  • Low RFS is related. ***, P ⁇ 0.001.
  • Example 3 Loss of SMS2 activity can effectively inhibit IL-4 induced M2 polarization of macrophages
  • M-CSF macrophage colony stimulating factor
  • the cells were plated in a 10 cm petri dish or a 12-well plate and cultured for three days. On the third day, fresh BMDM growth medium was replaced. After the cells were cultured for 7 days, flow cytometry was used to detect the expression of CD11b and macrophage general marker protein molecule F4/80 to evaluate the formation of mature BMDM (the conditions for inducing differentiation of BMDM in subsequent examples are the same).
  • the 1640 complete medium containing 20ng/mL interleukin-4 (IL-4, a classic macrophage type 2 polarization inducing factor) was used to induce cell polarization for 48 hours (48h).
  • IL-4 interleukin-4
  • Flow cytometry was used to detect the expression of M2 macrophage surface marker proteins (F4/80 and CD206), and real-time fluorescent quantitative PCR was used to detect the expression level of M2 related marker genes.
  • Wild-type C57bl/6j mice (WT group) ) BMDM is used as the control group, and the SMS2 knockout mouse BMDM is represented by the KO group.
  • SMS2 gene knockout does not affect the differentiation and maturation of BMDM cells (as shown in Figure 6A), but can significantly inhibit IL-4 induced type 2 polarization marker protein molecule CD206 (Figure 6B) and the marker protein arginase 1 (Arg1) ( Figure 6C) expression (using ⁇ -actin ( ⁇ -actin) as an internal reference), and a series of marker molecules of type 2 polarization (chitinase 3-like molecule (YM1), transforming growth factor - ⁇ (TGF- ⁇ )) gene expression level also showed a significant decrease (Figure 6D), but the effect of IL-4 did not have an effective effect on the expression of macrophage type I polarization marker protein molecule CD86 ( Figure 7).
  • control represents the normal control group
  • DMSO is the inhibitor solvent, and is used as the sample control group.
  • Compound I can effectively inhibit the type 2 polarization of macrophages induced by IL4 at a safe experimental dose.
  • BMDM BABLC mouse bone marrow primary macrophages
  • RAW 264.7 containing 10% fetal bovine serum
  • Compound I was added to make the final concentration 10 ⁇ M. After the cells were incubated for 1 hour, 20ng/mL IL-4 was added and the cells were cultured for 48 hours.
  • Example 5 Compound I can significantly reduce the M2 type polarization of BMDM cells induced by the conditioned medium of TNBC cells without affecting the M1 type polarization.
  • the selected representative triple-negative breast cancer cell lines (4T1 and MDA-MB-231) were cultured in 1640 complete medium. After the cells were 80% confluent, the cells were collected and resuspended to a final concentration of 2 ⁇ 10 6 cells. /mL, take 10mL cell suspension and plant it in a 10cm petri dish, continue culturing for 72 hours, collect the cell culture supernatant, centrifuge and filter it as a conditioned medium (4T1-CM and MDA-MB-231-CM) for BMDM Culture to simulate the microenvironment of tumor growth.
  • Example 6 Compound I can inhibit the secretion of IL-10 and TGF- ⁇ in BMDM cells induced by the conditioned medium of TNBC cells.
  • Macrophages in the tumor microenvironment are stimulated by a variety of factors.
  • type 2 polarization occurs, and on the other hand, they secrete a variety of anti-inflammatory and tumor-promoting cytokines, such as interleukin-10 (IL-10) and TGF- ⁇ .
  • ELISA method was used to determine the secretion of IL-10 and TGF- ⁇ after BMDM cells were induced and cultured with conditioned medium 4T1-CM and MDA-MB-231-CM. The results showed that after BMDM was treated with Compound I, the secreted IL-10 and TGF- ⁇ were significantly reduced (Figure 12A and Figure 12B).
  • Example 7 The regulatory effect of Compound I on the differentiation of BMDM cells in the tumor microenvironment may be related to the mTOR1 signaling pathway.
  • Example 8 Compound I reduces the migration ability of 4T1 cells induced by M2 type macrophages.
  • BMDM was resuspended in culture medium and adjusted to a density of 2.5 ⁇ 10 5 cells/mL. Plant 2mL per well in a 6-well plate, culture for 24 hours and then change the medium.
  • the SMS2 inhibitor group was pretreated with compound I at a final concentration of 10 ⁇ M for 1 hour, and then 20ng/mL IL-4 was added to induce induction BMDM is polarized, and the control group is pretreated with DMSO for 1 hour, then isotonic phosphate buffered saline (PBS) is added, and the culture is continued for 48 hours. Afterwards, the medium of each well was replaced with 2 mL of fresh 1640 medium, and the culture was continued for 24 hours.
  • PBS isotonic phosphate buffered saline
  • the culture supernatant of each well was collected, filtered and used for the transmembrane migration experiment of 4T1 cells (Transwell experiment).
  • Example 9 Oral administration of Compound I can effectively reduce the level of plasma SM in mice.
  • mice aged 6-8 weeks were randomly divided into two groups, 8-9 mice in each group.
  • the mice in the SMS2 inhibition group were given 20 mg/kg compound I daily, and the mice in the control group were given daily gavage.
  • 0.5% sodium carboxymethylcellulose (control) monitor the SM content in mouse plasma twice a week (detected by ELISA kit), after 14 days of intragastric administration of compound I, the total SM level in plasma showed a significant decrease ( Figure 15).
  • Example 10 Oral administration of Compound I can effectively inhibit the blood metastasis of TNBC cells in model mice, and improve the infiltration of TAMs and MSDCs in the tumor microenvironment, and this effect has an effect on the state of macrophages in the non-tumor microenvironment No effect.
  • the experimental mice were randomly divided into two groups.
  • the administration group was given compound I (20 mg/kg/day) by intragastric administration for two weeks in advance, and the fluorescein-labeled cells 4T1-luc cultured in vitro were collected and resuspended in pre-cooled PBS. 1 ⁇ 10 6 cells were injected into the tail vein of mice.
  • the fluorescence signal in the lungs of the mice was detected with an in vivo imager.
  • the fluorescence signal in the lungs of the mice was detected again.
  • the SMS2 inhibitor group was given compound I 20 mg/kg/day by intragastric administration until the end of the experiment, and the control group was given an equal amount of solvent (DMSO).
  • IHC staining was used to analyze the expression of macrophage marker protein F4/80 and M2 macrophage marker protein CD206 in lung metastases.
  • Immunohistochemistry (IHC) and immunofluorescence (IF) double staining was used to analyze the expression of regulatory T cell marker proteins FOXP3 and CD4, as well as the bone marrow-derived suppressor cell marker proteins CD11b and Gr1 (myelodifferentiation antigen 1).
  • Immunohistochemical staining was also used to detect the content of type 2 macrophages and killer T cells in the tumor environment. From the results ( Figure 20A and Figure 20B), it can be seen that the expression of macrophage general protein F4/80 was not significantly different between the two groups of tumors, but the expression of M2 type marker protein CD206 was significantly decreased in the compound I administration group, and CD206 and The ratio of F4/80 was also significantly reduced, indicating that Compound I did not affect the total number of macrophages infiltrated in tumor tissues. But it can effectively inhibit M2 type macrophages infiltrating in tumor tissues (Figure 20B). The present invention also detects the content of killer CD8 + T lymphocytes in tumor tissues. As shown in FIG.
  • oral administration of Compound I can effectively reduce the level of plasma SM in mice, and at the same time improve the tumor growth of TNBC, reduce the infiltration of M2 type macrophages in tumor tissues, increase killer immune cells, and block The normal growth of blood vessels in the tumor has played a role in the treatment of TNBC.

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Abstract

L'invention concerne l'application d'un inhibiteur de SMS2 dans la préparation d'un médicament pour le traitement d'un cancer du sein hautement invasif. Selon des expériences globales faisant intervenir des cellules 4T1 dans le but d'établir un modèle de cancer du sein triple négatif chez la souris et des expériences in vitro faisant intervenir des macrophages de moelle osseuse primaires provenant de souris, il est confirmé que le composé I, en tant qu'inhibiteur spécifique de SMS2, est capable d'inhiber efficacement la polarisation de type 2 des macrophages par diminution de l'activité de la sphingomyéline synthase 2 et des niveaux de sphingolipide in vivo, et est capable de remodeler un microenvironnement tumoral par réduction des macrophages de type M2 dans le microenvironnement tumoral du cancer du sein triple négatif et par réduction de l'étendue de l'infiltration d'autres cellules immunosuppressives dérivées de myéloïde, ce qui permet d'inhiber la croissance in situ du cancer du sein triple négatif ainsi que la formation et la croissance de métastases pulmonaires provoquées par la circulation sanguine. L'inhibition de l'activité de SMS2 peut être utilisée pour prévenir et traiter des cancers du sein malin hautement invasifs, dont le cancer du sein triple négatif.
PCT/CN2021/091931 2020-05-06 2021-05-06 Application d'un inhibiteur de sms2 dans la préparation d'un médicament pour le traitement du cancer du sein hautement invasif WO2021223713A1 (fr)

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