Specific galactoside inhibitors of galectin-1

Abstract

The present invention relates to compounds of formula (I) for use in a method of treating a cancer with higher expression of galectin-1 compared to normal tissue.

Description

Technical Field

[0001] This invention relates to compounds of formula (I),

[0002] (I); In a method for treating cancers with higher expression of galactolectin-1 compared to normal tissues. Furthermore, oral compositions are involved. The invention also relates to a method for treating cancer. Background Technology

[0003] Galactolectins are a family of lectins that mediate a variety of biological functions in health and disease. Due to their solubility, galactolectins are present in the extracellular space, cytosol, and nucleus, and can function both intracellularly and extracellularly. Galactolectins bind to β-galactosidase, a common glycan modification on many cell surface receptors, which regulates cellular function by altering receptor-mediated signal transduction pathways (Liu, 2005; Rabinovich and Toscano, 2009). Galactolectins can also bind to intracellular interactants in a non-carbohydrate-dependent manner, with different members of the galactolectin family having different binding partners (Liu and Stowell, 2023). Fifteen members of the galactolectin family (eleven in humans) are classified according to the number and arrangement of their carbohydrate recognition domains (CRD). One prototype galectin was found, existing as a monomer or homodimer (galectin-1, galectin-2, galectin-5, galectin-7, galectin-10, galectin-11, galectin-13, galectin-14, and galectin-15); chimeric galectin-3 possesses a CRD and an amino-terminal domain capable of forming oligomers; tandem repeating galectins (galectin-4, galectin-6, galectin-8, galectin-9, and galectin-12) contain two distinct CRDs linked by amino acid linkers and exist as monomers or dimers (Cummings et al., 2009; Sciacchitano et al., 2018; Seyrek, Richter and Lavrik, 2019; Liu and Stowell, 2023).

[0004] Galactolectin-1 regulates physiological and disease-related processes, including tissue growth, cell proliferation, apoptosis, angiogenesis, inflammation, and carcinogenesis (Perillo et al., 1995; Cousin and Cloninger, 2016; Yu et al., 2023). In inflammation, galactolectin-1 is generally considered immunosuppressive because it can induce apoptosis of effector T cells, antagonize T cell receptor signaling, block T cell-extracellular matrix interactions, and activate regulatory T cell populations (Perillo et al., 1995; Rabinovich GA et al., 1999; Liu et al., 2009; Cutine et al., 2021). Galactolectin-1 also polarizes macrophages to the anti-inflammatory “M2” type and limits the production of reactive oxygen species in neutrophils (Correa et al., 2003; Rodrigues et al., 2019). In the tumor microenvironment, this suppression of T cells may particularly contribute to tumor persistence. Galactochonin-1 is associated with other cancer markers, including promoting tumor angiogenesis, connective tissue proliferation, and hypoxia (Ito et al., 2012; Griffioen and Thijssen, 2014; Kuo and Le, 2014; Martínez-Bosch et al., 2014; Stanley, 2014; van Beijnum et al., 2016).

[0005] Several preclinical and clinical studies are underway using galectin-3 inhibitors for the treatment of cancer and chronic inflammatory diseases, some of which have shown or been proposed to bind to galectin-1 (Laderach and Compagno, 2023). However, due to the weaker affinity of these molecules for galectin-1 than for galectin-3 and the lack of reliable pharmacological characterization, it is difficult to determine the therapeutic efficacy of the additional inhibitory effect of these molecules on galectin-1. Although galectin-1 expression is known to vary across different cancer types, the specific role of galectin-1 in cancer is poorly understood, although some analyses have demonstrated a correlation between high galectin-1 expression in cancer and overall survival (e.g., in pancreatic and gastric cancer) (Thijssen et al., 2015; Liu et al., 2020). Several studies have demonstrated the potential efficacy of galectin-1 inhibitors in preclinical settings, including in vitro human bone and lung cancer cells and in vivo xenograft models of neural tube defects (Goud et al., 2019, 2020; Shih et al., 2019). Blocking galectin-1 with monoclonal antibodies resulted in reduced tumor size in immunocompetent mice carrying xenografted lung or melanoma tumors (Croci et al., 2014). In a mouse oral cancer model, antibody blockade of galectin-1 reduced tumor volume and increased T cell infiltration into the tumor (Nambiar et al., 2019). Summary of the Invention

[0006] In a first aspect, the present invention relates to compounds of formula (I),

[0007] (I); This is used in methods for treating cancers that express galactolectin-1 at higher levels compared to normal tissues. In this article, normal tissue refers to mammalian tissue, such as human tissue, from a subject without cancer.

[0008] In one embodiment, the cancer is a solid tumor, which is reduced by the treatment. In another embodiment, the compound of formula I also inhibits immunosuppressive cytokines, wherein the cytokines include at least IL-17, IL-10, and IL-6.

[0009] In another embodiment, the compound of formula (I) is 3,4-dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside.

[0010] In another implementation, the cancer is selected from sarcoma, mesothelioma, glioblastoma, carcinosarcoma, adenocarcinoma, adrenocortical cancer, malignant carcinoma, and melanoma.

[0011] In another implementation, the cancer is melanoma.

[0012] In another implementation, the cancer is a malignant epithelial tumor.

[0013] In another implementation, the cancer is breast invasive carcinoma.

[0014] In another implementation, the cancer is skin cutaneous melanoma.

[0015] In another embodiment, treatment is administered orally with the compound of formula (I). Typically, the compound of formula I is administered to a human subject at a daily dose of 10 mg to 2000 mg. In another embodiment, the compound of formula I is administered twice daily at a unit dose of 5 mg to 1000 mg. In another embodiment, the compound of formula I is administered to a human subject at a daily dose of 50 mg to 600 mg. In another embodiment, the compound of formula I is administered twice daily at a unit dose of 25 mg to 300 mg.

[0016] In a second aspect, the present invention relates to an oral pharmaceutical composition comprising a compound of formula I (3,4-dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside), and optionally pharmaceutically acceptable additives.

[0017] In another embodiment, the oral pharmaceutical composition of the second aspect is selected from tablets, pills, capsules, granules, solutions, or suspensions.

[0018] In a third aspect, the present invention relates to a method for treating cancers with elevated galactolectin-1 expression, comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal (e.g., a human) in need.

[0019] (I). Attached Figure Description

[0020] Figure 1GB1908 is a galectin-1 inhibitor that reduces the expression of galectin-1 on the surface of mouse macrophages. The selectivity of GB1908 for human and mouse galectin-1, galectin-3, galectin-9N, and galectin-9C is shown in Figure A. Extracellular galectin-1 (B) and galectin-3 (C) were measured by flow cytometry on mouse bone marrow-derived macrophages after 2 hours of incubation with a series of doses of GB1908 (B). Data are shown as the percentage change in mean fluorescence intensity (MFI) from control samples. Each point represents one mouse; bar graphs represent mean + / - SEM. An asterisk indicates significance using one-way repeated measures ANOVA.

[0021] Figure 2 Galectin-1 expression is associated with low survival rates in breast cancer and melanoma, and inhibition of galectin-1 in vivo can reduce tumor size. Cancers with the highest galectin-1 expression, according to TCGA; n = 57–1062 biopsies per cancer type (A). High expression of galectin-1 (LGALS1) is associated with low survival rates in patients with invasive breast cancer (B) and malignant melanoma of the cutaneous tumor (metastatic) (C). Homologous mouse models of breast cancer (D) and melanoma (E) were used to assess the effect of GB1908 on tumor volume. Unpaired t-tests with multiple corrections were used; asterisks in C and D indicate statistical significance at each time point. Thick lines with error bars represent mean + / - SEM; thin lines represent data per mouse.

[0022] Figure 3 Immunomodulatory effects of galactolectin-1 and galactolectin-3 inhibitors GB1908 and GB1211, and pembrolizumab, in an in vitro stromal NSCLC tumor microenvironment model. Primary human immune cells and fibroblasts were co-cultured with NSCLC cell lines and treated with GB1211 (A), GB1908 (B), or pembrolizumab at doses ranging from 25 μg / mL (C, black line; red line for comparison, 10 μM GB1908). Biomarkers are listed on the x-axis; changes in each biomarker compared to the control group (grey “envelope”, n=6) are shown as logarithmic transformations of drug-treated samples (n=3 per dose). Annotated biomarkers indicate at least one drug concentration with an effect size >20% and a p-value <0.01 compared to the control group. The prefix “s” indicates soluble biomarkers measured in cell culture supernatant.

[0023] Figure 4GB1908 reduced the production of IL-17 and IFN-γ in stimulated mouse and human T cells. T lymphocytes isolated from human whole blood (A, C, E) or mouse spleens (B, D, F) were stimulated with anti-CD3 and anti-CD28 and GB1908 at dose ranges (left column). IL-17 (AB), IFN-γ (CD), and TNFα (EF) were measured in the supernatant after 48 hours. Bar plots show mean + / - SEM, with each point representing one donor (n=3). Data show the percentage change in cells treated with control (DMSO) for each donor. An asterisk indicates significance using a one-way ANOVA analysis with repeated measures.

[0024] Figure 5 GB1908 reduces cytokine production in mice with concanavalin-A (an acute inflammation model). Study Abstract (A). IL-17A, IFN-γ, IL-6, and TNFα in terminal blood samples were measured using the LEGENDPlex assay (BE). Bar graphs represent mean + / - SEM, with each point representing one mouse. Asterisks indicate significance using an unpaired t-test (mediator vs. GB1908). Detailed Implementation

[0025] The compound of formula I is a specific inhibitor of galectin-1. This inhibitor exhibits higher selectivity for galectin-1 than for galectin-3, galectin-9N, and galectin-9C. Figure 1 A), and has similar affinity for mouse and human galactoglucosinolates (Table 1).

[0026] Table 1: Binding affinity of compounds to human and mouse galactolectins. KD values ​​(nM) are shown using SEM (if available).

[0027] An oral formulation was developed for administration to mice in in vivo studies, making it a useful compound for preclinical research. The targeted binding of galactolectin-1 was investigated by evaluating a reduction in galactolectin-1 expression on mouse bone marrow-derived macrophages. Treatment with the compound of formula I resulted in a dose-dependent reduction of galactolectin-1 on the cell surface, as measured by flow cytometry. Figure 1 B). Galactolectin-3 remained unchanged, demonstrating the specificity of this compound. Figure 1 C).

[0028] It is known that galectin-1 expression varies across different cancer types (Cousin and Cloninger, 2016). The Cancer Genome Atlas (TCGA) dataset contains gene expression data from cancer and normal tissue samples from a cohort of 11,000 patients, encompassing 33 different tumor types. To investigate which cancers would benefit from galectin-1 inhibitor therapy, TCGA was mined to identify cancers with the highest galectin-1 (LGALS1) expression. Figure 2 A). TCGA metadata also includes overall and progression-free survival. The association between galactolectin-1 expression and progression-free survival was analyzed in two cancer types: invasive breast cancer and metastatic melanoma of the skin. For both cancers, high expression of galactolectin-1 was associated with a lower probability of survival. Figure 2 B, C).

[0029] The relationship between galactolectin-1 and tumor progression, and its association with reduced survival probability, suggests that inhibiting galactolectin-1 may offer potential therapeutic advantages in treating these types of cancer. To test this hypothesis, compounds of Formula I were used in two syngeneic mouse models: breast cancer and melanoma. Mouse breast cancer cell line 4T1 or mouse melanoma adenocarcinoma cell line B16-F10 were cultured and implanted into the mammary fat pads of mice. Twenty-four hours later, mice were treated with either the compound of Formula I (30 mg / kg) or the carrier, and tumor size was monitored using calipers. In the breast cancer model ( Figure 2 D) and melanoma model ( Figure 2 In E), treatment with the compound of formula I reduced the tumor volume.

[0030] Besides directly influencing tumor progression mechanisms, galactolectin-1 is a known modulator of inflammatory responses, particularly T cells, and can also alter the immune response to tumors. The mechanism of action of compounds of Formula I in the tumor immune microenvironment was investigated using the in vitro BioMAP system (Eurofins Discovery, CA, USA). A model of stromal tumor microenvironment (“StroNSCLC”) was generated by co-culturing human peripheral blood mononuclear cells, human primary dermal fibroblasts, and the H1299 non-small cell lung cancer (NSCLC) cell line with T cell receptor ligands. Changes in biomarkers were assessed 48 hours after treatment with compounds of Formula I. Treatment with GB1211 (a galactolectin-3 inhibitor currently in NSCLC trials (Aparisi et al., 2023)) and pembrolizumab (a PD-1 inhibitor used to treat a variety of cancers) was also evaluated and compared. The galactolectin-3 inhibitor GB1211 (… Figure 3A) Upregulated several biomarkers, including IL-6 and IFNγ (IFNg), at 10 μM. However, the compound of formula I exhibits different immunomodulatory properties, inhibiting the expression of many immunosuppressive proteins at 10 μM, particularly IL-17, IL-10, and IL-6 (IFNg). Figure 3 The expression of formula I is also present. Compounds of formula I also exhibit similarity to pembrolizumab (B). Figure 3 The different characteristics compared to C) indicate different mechanisms of action that can be used as complementary therapies.

[0031] Prior to in vivo studies, further in vitro studies were conducted to determine whether the galactoglobulin inhibitor resulted in similar changes in cytokine production in mouse and human T cells. T cells cultured from human whole blood and mouse spleen were stimulated with anti-CD3 and anti-CD28 to induce cytokine production and co-cultured with compounds of Formula I at specific dose ranges for 48 hours. Compounds of Formula I inhibited IL-17 in mouse and human T cells in a dose-dependent manner. Figure 4 AB), IFNγ ( Figure 4 CD) and TNFα Figure 4 (EF). The data also indicate that the reduction in cytokines observed using the BioMAP system is at least partly due to the effect of the compound of formula I on T cells.

[0032] Because compounds of Formula I exhibit similar effects in inhibiting cytokines in activated T cells in mice and humans, an in vivo mouse model of T cell-mediated inflammation was utilized. Concanavalin A (con-A) induces acute liver injury by directly activating T lymphocytes, which are then recruited to the liver (Heymann et al., 2015). Elevated inflammatory cytokines resulting from the induced inflammatory response can be measured in circulation. In this model, the effect of galactolectin-1 inhibition on cytokines was assessed by pretreating mice with either a compound of Formula I or a mediator (control) 1 hour prior to con-A injection. Figure 5 A). Terminal blood samples were collected 8 hours after con-A injection for analysis. All cytokines measured in con-A-treated mice were upregulated compared to untreated pups. IL-17A, IFNγ, IL-6, and TNFα were all decreased in mice treated with the compound of Formula I compared to mice treated with the agonist. Figure 5 BE).

[0033] In in vitro and in vivo studies, compounds of Formula I (a high-affinity and selective inhibitor of galactolectin-1) have been clearly demonstrated to reduce tumor growth and downregulate several immunosuppressive cytokines in mouse cancer models. Data mining of the literature was used to generate a comprehensive overview of pathways regulated by galactolectin-1 in tumor cells and the surrounding stroma that promote cancer progression. In tumor-associated endothelial cells, galactolectin-1 upregulates angiogenesis; in cancer-associated fibroblasts, galactolectin-1 promotes connective tissue proliferation. In tumor cells, galactolectin-1 regulation is involved in pathways related to epithelial-to-stromal cell transformation, cancer cell migration and invasion, and metastasis.

[0034] Several signaling pathways regulated by galectin-1 also have downstream effects on the inflammatory response. In cancer cells and endothelial cells, galectin-1 induces ERK1 / 2 signaling, which some studies have shown leads to upregulation of NF-κB activity (Dhawan and Richmond, 2002; Huang et al., 2014; Chen et al., 2016). Since IL-6 and TNFα are upregulated by NF-κB, the reduction of these cytokines observed in our in vitro experiments and mouse studies may be due to inhibition of this pathway by compounds of formula I. Galectin-1 also induces SDF-1 production in tumor stromal cells such as pancreatic stellate cells; literature suggests that SDF-1 signaling upregulates IL-6 production via CXCR4 (Tang et al., 2008; Lu et al., 2009; Chen et al., 2011; Thomas et al., 2015). Galactoglobulin-1 activates tissue plasminogen activator (tPA), which upregulates the conversion of plasminogen to plasmin (Roda et al., 2009).

[0035] It has been shown that treatment with compounds of formula I reduces several known immunosuppressive cytokines in the tumor microenvironment. IL-17 is involved in tumor progression across multiple cancer types through various mechanisms, including upregulation of cancer cell migration and metastasis, recruitment of myeloid-derived suppressor cells to induce angiogenesis and suppress antitumor immunity, and increased PD-L1 expression (Zhao et al., 2019; Cui et al., 2021; Liao et al., 2023). In a mouse model of colorectal cancer, increased PD-L1 promotes resistance to immune checkpoint inhibitor therapy, and blocking IL-17A improves the efficacy of anti-PD-1 therapy (Liu et al., 2021). In a mouse myeloma transplantation model, pharmacological inhibition or gene depletion of IL-17A improves prognosis (Vuckovice et al., 2019). In breast cancer, IL-17 expression on γ-δ T cells leads to suppression of the recruitment of neutrophils into cytotoxic T cells, thereby promoting metastasis (Coffelt et al., 2015; Wu et al., 2020).

[0036] Similarly, IL-6 is also associated with poorer outcomes in many cancers. IL-6 drives the JAK / STAT3 signaling pathway, suppressing tumor-killing NK cells, effector T cells, and dendritic cells while upregulating regulatory T cells and myeloid-derived suppressor cells, creating an immunosuppressive environment (Johnson, O'Keefe and Grandis, 2018). In patients with advanced breast, kidney, and bladder cancer, elevated IL-6 levels are also associated with adverse responses to atezolizumab (an anti-PD-L1 antibody), while in mouse models, combined blockade of PD-L1 and IL-6 receptors improved prognosis compared to atezolizumab alone (Huseni et al., 2023). IL-6 production in tumor cells and related fibroblasts, endothelial cells and dendritic cells is upregulated by IL-17. In mouse models, IL-6 blockade reduces Th17 cells and improves prognosis (Wang et al., 2009; Hailemichaeel et al., 2022).

[0037] The compounds of Formula I block immunosuppressive biomarkers differently from the galectin-3 inhibitor GB1211, which has shown promise in clinical trials for non-small cell lung cancer (NSCLC) (Aparisi et al., 2023). In NSCLC, galectin-3 expression is highly correlated with poor response to checkpoint inhibitor therapy (Capalbo et al., 2019). Galectin-3 enhances the interaction between PD-1 / PD-L1 and reduces the affinity for the immune checkpoint inhibitors pembrolizumab and atezolizumab, an effect reversed by GB1211 (Mabbitt et al., 2023). The unique mechanism by which GB1211 overcomes resistance to checkpoint inhibitor therapy appears to be specific to its galectin-3 inhibition. Furthermore, the expression of galectin-1 and galectin-3, and their correlation with survival, varies considerably across different cancers. Studies have identified breast cancer and metastatic cutaneous melanoma as cancers with high expression of galactolectin-1, and galactolectin-1 is associated with poor survival prognosis, suggesting that these cancers may benefit from galactolectin-1 inhibitor therapy. Considering the types of cancer for which these drugs will be tested could increase the likelihood of successful clinical trials.

[0038] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient in order to combat a condition (e.g., disease or disorder). The term is intended to encompass all treatment of a given condition suffered by a patient, such as the administration of active compounds to alleviate symptoms or complications, slow the progression of the disease, disorder, or symptom, reduce or alleviate symptoms and complications, and / or cure or eliminate the disease, disorder, or symptom, as well as prevention of the condition. Prevention should be understood as the management and care of a patient for the purpose of combating a disease, symptom, or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications. Treatment can be administered in an acute or chronic manner. Patients to be treated are preferably mammals; particularly humans, but may also include animals such as dogs, cats, cattle, sheep, and pigs.

[0039] As used herein, the term "therapeutic effective amount" of a compound of formula (I) of this invention refers to an amount sufficient to cure, alleviate, or partially suppress the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this purpose is defined as a "therapeutic effective amount." The effective amount for each purpose will depend on the severity of the disease or injury, as well as the subject's weight and general condition. It should be understood that appropriate dosages can be determined using standard experimental methods, by constructing a numerical matrix and testing the differences in the matrix, within the scope of the common skill of a trained physician or veterinarian.

[0040] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and optionally a pharmaceutically acceptable additive, such as a carrier or excipient.

[0041] As used herein, "pharmaceuticalally acceptable additives" are intended to include, without limitation, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, etc., that a person skilled in the art would consider using when formulating the compounds of the present invention to prepare pharmaceutical compositions.

[0042] The adjuvants, diluents, excipients, and / or carriers that can be used in the compositions of the present invention must be pharmaceutically acceptable, i.e., compatible with the compounds of formula (I) and other components of the pharmaceutical composition, and harmless to the recipient. Preferably, the composition should not contain any substances that may cause adverse reactions (e.g., allergic reactions). The adjuvants, diluents, excipients, and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0043] As described above, in addition to the compounds disclosed herein, the compositions disclosed herein, particularly pharmaceutical compositions, may also contain at least one pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier. In some embodiments, the pharmaceutical composition comprises 1 to 99% by weight of the at least one pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier, and 1 to 99% by weight of the compounds disclosed herein. The total amount of the active ingredient and the pharmaceutically acceptable adjuvant, diluent, excipient, and / or carrier does not exceed 100% by weight of the composition, particularly the pharmaceutical composition.

[0044] In some implementations, only one of the compounds disclosed herein is used for the above purposes.

[0045] In some embodiments, two or more of the compounds disclosed herein are combined for the above-mentioned purposes.

[0046] The compositions, particularly pharmaceutical compositions comprising the compounds described herein, are suitable for oral, intravenous, topical, intraperitoneal, intranasal, oral, sublingual, or subcutaneous administration, or for administration via the respiratory tract, for example, in the form of aerosols or air-suspended fine powders. Therefore, the pharmaceutical compositions may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches, or suppositories.

[0047] Other implementations of the method are described in the experimental section of this paper, and each individual method and each raw material constitutes an implementation that can form part of the implementation.

[0048] The above embodiments should be considered as relating to any aspect described herein (e.g., "treatment method", "pharmaceutical composition", "compound used as a medicine" or "compound used in a method"), and any embodiment described herein, unless specifically stated that the embodiments relate to one or more aspects of the invention.

[0049] All references cited in this article, including publications, patent applications and patents, are cited as if each reference were individually and specifically indicated as cited as reference and are fully elaborated in this article.

[0050] All headings and subheadings used herein are for convenience only and should not be construed as limiting the invention in any way.

[0051] This invention includes any combination of the above-described elements in all possible variations, unless otherwise stated herein or clearly contradicted by the context.

[0052] The terms “a,” “an,” and “the,” as used in the context of describing this invention, and similar designations, shall be construed as encompassing both the singular and plural, unless otherwise stated herein or clearly contradicted by the context. The terms “a” and “an” mean “one or more” and may be used interchangeably with “at least one.”

[0053] Unless otherwise stated herein, the descriptions of numerical ranges herein are intended only as a shorthand for individually referring to each individual value falling within that range, and each individual value is incorporated into the specification as if it were described individually herein. Unless otherwise stated, all precise values ​​provided herein represent corresponding approximations (e.g., all precise exemplary values ​​provided with respect to a particular factor or measurement may also be considered to provide corresponding approximate measurements, modified with “about” where appropriate).

[0054] Unless otherwise stated in this document or clearly contradicted by the context, all methods described herein may be performed in any suitable order.

[0055] Unless otherwise stated, the use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is merely for the purpose of better illustrating the invention and does not constitute a limitation on the scope of the invention. No language in the specification should be construed as indicating that any element is essential to the implementation of the invention unless equally expressly stated otherwise.

[0056] The patent documents cited and incorporated in this article are for convenience only and do not reflect any opinion on the validity, patentability and / or enforceability of these patent documents.

[0057] The term “and / or” as used in this document is intended to indicate two options and each option. For example, the expression “xxx and / or yyy” means “xxx and yyy”; “xxx”; or “yyy”, all three options depending on their respective implementation schemes.

[0058] The description of any aspect or embodiment of this invention uses terms relating to one or more elements, such as "comprising," "having," "including," or "containing," intended to support similar aspects or embodiments of the invention, namely "consisting of," "consisting substantially of," or "substantially comprising," unless otherwise stated or clearly contradicted by the context (e.g., a composition described herein as comprising a specific element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by the context). To the fullest extent permitted by applicable law, this invention includes all modifications and equivalents to the subject matter set forth in the aspects or claims herein.

[0059] The invention is further illustrated by the following embodiments; however, these embodiments should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and the following embodiments, whether individually or in any combination, are important for implementing the invention in different forms.

[0060] experiment The compounds of Formula I described herein can be prepared as disclosed in Example 9 of WO0221 / 001528. In this document, the compounds of Formula I are also referred to as GB1908.

[0061] Another compound, 5-bromopyridin-3-yl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, has the following structure: , It can be prepared as disclosed in WO2021 / 122719. In this document, the compound is also referred to as GB1211.

[0062] C57BL / 6 mice were purchased from Charles River. C57BL / 6 mice were euthanized using approved methods, and the femur and tibia were dissected and cleaned. Epiphyses were sequentially removed from each bone, and bone marrow cells were collected by rinsing each bone with a needle and a syringe filled with sterile PBS. All bone marrow cells from each mouse were pooled. Cells were filtered through a 100 μm cell filter and cultured in 6-well cell culture plates at 37°C in medium containing 5% CO2 (DMEM + 10% FBS + 1% penicillin-streptomycin + 2 mM L-glutamine + 20 ng / mL M-CSF). On days 4 and 6 post-isolation, cells were washed twice with sterile PBS and fresh culture medium was added.

[0063] Cells were cultured for 7 days before experiments were performed. Cells were washed with trypsin-EDTA and a cell scraper and separated from the wells, then resuspended in DMEM-only medium. Viable cell counts were performed using Trypan Blue, and the medium volume was adjusted to produce a cell suspension of 1 million viable cells per mL. Cells were transferred to 2 mL Eppendorfs (500 μL per tube) containing either the compound of Formula I or diluted DMSO (control). Cells were incubated at 37°C for 2 hours with gentle agitation (300 rpm).

[0064] After incubation, cells were stained with Zombie-UV active dye (1:1000 in PBS) and incubated in the dark at room temperature for 30 minutes. Cells were centrifuged at 300×g for 5 minutes, and the supernatant was discarded. 2 μL of FC-block was added to the remaining volume, cells were gently resuspended, and incubated at room temperature for 5 minutes. 1 μL of each of the following antibodies was added directly to the remaining volume / Fc block: CD11b (Brilliant Violet 605), F4 / 80 (Alexa Fluor 700), galactoglobulin-3 (FITC), and galactoglobulin-1 (PE). Samples were incubated at 4°C for 20 minutes. 1 mL of FACS cell staining buffer was added to each sample, and the sample was centrifuged at 300×g for 5 minutes. Samples were resuspended in 300 μL of FACS cell staining buffer and stored on ice until analysis. BD FACSDiva was used. TM The software uses the BD LSR Fortessa (5 laser) analyzer to analyze the sample.

[0065] Syngeneic mouse cancer model Mice were kept in individual, ventilated cages at 22°C and 45-65% relative humidity for 12 hours of light / dark cycles.

[0066] The mouse breast cancer cell line 4T1 was cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin, and incubated at 37°C and 5% CO2. The mouse melanoma adenocarcinoma cell line B16-F10 was cultured in DMEM high-glutamine 1, 10% fetal bovine serum, and 1% penicillin / streptomycin, and incubated at 37°C and 10% CO2. When confluenced, 10,000 4T1 cells in 100 μL PBS were implanted into the left mammary fat pad of female BALB / c mice (n=16), or 20,000 B16-F10 cells were implanted into female C57BL / 6N mice (n=16).

[0067] Starting one day after tumor cell implantation, mice in both tumor models were treated with the same dosing regimen. The mediator group (n=8) received 5 mL / kg PBS intraperitoneally three times daily at 3-4 day intervals. The GB1908 group (n=8) received 30 mg / kg of compound I in PEG 300 + Solutol HS15 + Tween 20 (ratio 84 / 15 / 1) twice daily via oral feeding. Tumor size was assessed twice weekly using calipers and calculated as follows: width 2 × length / 2.

[0068] BioMAP StroNSCLC Non-small cell lung cancer cell line NCl-H1299 and human neonatal skin fibroblasts were cultured in 96-well plates until confluence. Primary human peripheral blood mononuclear cells (PBMCs) were collected from multiple donors (n=3–6) and added to the plates. Compounds GB1211 and Formula I were prepared in DMSO and added to the wells. A diluted DMSO-only condition was used as a control. Each compound was tested three times. After 1 hour, submitotic superantigens were added to the wells. These antigens elicit T cells via T cell receptors but do not drive proliferation. Cells were incubated for 48 hours. Direct ELISA was used to measure cell-related and cell membrane biomarkers. Soluble biomarkers were measured using HTRF© assays, bead-based multiplex immunoassays, or capture ELISA.

[0069] Human and mouse T cell analysis For human body analysis, use EasySep. TM The human T-cell isolation kit isolates T cells from whole blood of donors from the Sygnature blood donor group. For mouse analysis, EasySep was used. TMT cells were isolated from the spleens of 6-12 week old male BALB / c mice from Charles River, UK, using a mouse T cell isolation kit. The isolated cells were resuspended in culture medium (RPMI 1640 containing only mouse cell culture medium with 10% inactivated fetal bovine serum, 1% penicillin-streptomycin, 1% glutamine, and 55 μM β-mercaptoethanol). 96-well plates were coated with 5 μg / mL anti-CD3 antibody. Compounds GB1211 and Formula I were prepared in DMSO and added to the wells at the desired concentration. Cells were added to the wells at a concentration of 100,000 cells / well. Cells were incubated for 30 minutes (37°C, 5% CO2), then anti-CD28 antibody was added to a final concentration of 1 μg / mL. Cells were then incubated for another 48 hours. The supernatant was harvested and stored at -80°C. The human and mouse 5-plex U-Plex kit for analyzing TNFα, IL-2, IL-6, IL-17A, and IFNγ was obtained from Meso Scale Discovery for cytokine analysis. Plates were read using a MESOQuickPlex SQ120MM instrument. Data were analyzed using MSD Workbench software.

[0070] Concanavalin A mouse model Male C57BL / 6 mice were administered orally via tube feeding at a dose of 10 mL / kg of either a compound of formula I dissolved in a carrier (30 mg / kg), GB1211 (10 mg / kg), or the carrier alone (84% PEG + 15% Solutol HS15 + 1% Tween-20). One hour later, mice were administered intravenously via peripheral vein con-A (Sigma, C5275; 9 mg / kg, dissolved in sterile saline at a concentration of 1.5 mg / mL). Mice were monitored throughout the study, and euthanized before the end of the study if moderate clinical symptoms appeared. Eight hours after con-A injection, mice were euthanized by overdose anesthesia (intraperitoneal), and blood was collected from the vena cava. Blood samples were centrifuged at 400 × g for 10 min without braking, plasma was removed, and the samples were stored at -20°C until analysis. BioLegend® LEGENDPlex was used according to the manufacturer's protocol. TM Plasma cytokines were measured in the mouse inflammation group. Data were acquired using a BD LSR Fortessa (5 laser) analyzer. Post-acquisition, data were analyzed using BioLegend® Qognit software.

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Claims

1. A compound of formula (I), （I） In methods for treating cancers that express galactolectin-1 at higher levels compared to normal tissues.

2. The compound of claim 1, wherein the cancer is a solid tumor, and the solid tumor is reduced by the treatment.

3. The compound of claim 2, wherein the compound of formula I further inhibits immunosuppressive cytokines, wherein the cytokines comprise at least IL-17, IL-10 and IL-6.

4. The compound according to any one of claims 1-3, wherein the compound of formula (I) is 3,4-dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside.

5. The compound according to any one of claims 1-4, wherein the cancer is selected from sarcoma, mesothelioma, glioblastoma, carcinosarcoma, adenocarcinoma, adrenocortical carcinoma, malignant epithelial tumor and melanoma.

6. The compound according to any one of claims 1-5, wherein the cancer is selected from malignant epithelial tumors and melanoma.

7. The compound according to any one of claims 1-6, wherein the cancer is selected from invasive breast cancer and malignant melanoma of the skin.

8. The compound according to any one of claims 1-7, wherein the treatment is performed by oral administration of the compound of formula (I).

9. The compound of claim 8, wherein the compound of formula I is administered to a human subject at a daily dose of 10 mg to 2000 mg.

10. The compound according to claim 8 or 9, wherein the compound of formula I is administered twice daily at a unit dose of 5 mg to 1000 mg.

11. An oral pharmaceutical composition comprising a compound of formula I as claimed in claim 1 and optionally a pharmaceutically acceptable additive.

12. The oral pharmaceutical composition according to claim 10, wherein the composition is selected from tablets, pills, capsules, granules, solutions or suspensions.

13. A method for treating cancers with elevated galactolectin-1 expression, comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal in need, such as a human. （I）。

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