Composition for protecting against radiation-induced salivary gland damage comprising MGEA5 inhibitor

Abstract

The present invention relates to a composition for protecting against radiation-induced salivary gland damage, the composition comprising an MGEA5 inhibitor and, more specifically, to a composition for protecting against or mitigating radiation, the composition comprising an MGEA5 inhibitor so as to capable of preventing the removal of O-GlcNAc, bound to a protein and involved in radiation-induced cell damage and death, to inhibit the phosphorylation of a target protein and thereby suppress the activity thereof. The composition can thus be used to prevent, alleviate, or treat radiation therapy-induced salivary gland damage.

Description

Composition for protecting salivary glands from radiation-induced damage comprising an MGEA5 inhibitor

[0001] The present invention relates to a composition for protecting salivary glands from radiation-induced damage, comprising an MGEA5 inhibitor.

[0002] The present invention is a research result of the "Discovery and optimization of salivary gland regeneration material simulating the branching morphogenesis mechanism of developing salivary glands" project of the Ministry of Education, Republic of Korea's Science and Technology Research Infrastructure Construction Project (Project Unique Number 1345363279, Project No. 2022R1I1A2068786) and the "Identification of the mechanism promoting early lesions in Sjogren's syndrome" project of the Ministry of Science and ICT, Republic of Korea's Individual Basic Research (MSIT) Project (Project Unique Number 1711183469, Project No. 2022R1C1C1006181).

[0003]

[0004] Ionizing radiation (IR) was first used for cancer treatment by Helsper in 1967. Radiation therapy utilizes the principle that radiation or radioisotopes destroy cancer cells and halt their growth. The problem is that radiation exposure can occur not only in cancer cells but also in surrounding normal tissues. Radiation exposure is known to induce apoptosis by inducing DNA repair, cell cycle abnormalities, and cell death. It is also known to cause chromosomal abnormalities in peripheral blood lymphocytes (PBLs), tissue and organ damage, birth defects, and cancer.

[0005] To address these issues, there has been growing interest in radioprotectors to protect the body from radiation exposure. From the 1950s to the 1980s, various derivatives of sulfhydryl compounds, known for their effective scavenging of reactive oxygen species, were studied for their synthesis and activity. However, their oral efficacy was limited, their toxicity was high, and their short half-lives hindered their widespread use. Subsequently, protease inhibitors, vitamins, metallo-elements, and calcium antagonists emerged. In the 1990s, attention was focused on the internal defense system, and various types of cytokines such as granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), IL-1, TNF-α, IL-6, stem cell factor (SCF), polysaccharides, and prostaglandins (PG) were investigated to elucidate the radioprotective effects, while active research is being conducted to increase efficacy by using various drugs with different mechanisms of action in combination. However, synthetic substances are highly toxic, and in the case of immunohematopoietic factors, they have many side effects and are expensive, limiting their practical use.

[0006] Head and neck cancer, in particular, has been reported to have a favorable response rate to radiation therapy, and in many cases, it is given priority over chemotherapy. While technologies such as improved radiation precision and new radiation sources are being developed to minimize damage to surrounding tissues, salivary glands, which are more radiosensitive than other tissues, are significantly damaged during radiation therapy for head and neck cancer patients, and this remains a serious problem. Although salivary glands are highly differentiated, slowly proliferating tissues, they are surprisingly sensitive to radiation therapy. Radiation frequently causes cell membrane destruction and cell death in salivary acinar cells. It is estimated that more than 80% of head and neck cancer patients receiving radiation therapy experience dry mouth and decreased salivary gland function. Salivary gland dysfunction can lead to functional changes such as dry mouth, difficulty chewing, dysphagia (dysphagia), loss of taste, mucositis, and oral infections, significantly reducing the patient's quality of life.

[0007] Treatment options for salivary gland dysfunction induced by radiation therapy are limited. Muscarinic receptor agonists such as pilocarpine and cevimeline, as well as artificial saliva, can be used, but their effectiveness is limited to temporary symptom relief. Amifostine is the only FDA-approved radioprotective agent to prevent damage to normal tissues, including salivary glands. However, its widespread use is hampered by side effects such as severe hypotension in approximately 30% of treated patients, toxicity, and potential tumor-protective effects. The development of novel radioprotective agents to replace amifostine is essential to improve the quality of life of patients with head and neck cancer and reduce societal costs.

[0008] O-GlcNAcylation is a reversible protein modification in which an N-acetyl-D-glucosamine residue is transferred to the hydroxyl group of serine and threonine residues, resulting in an O-GlcNAcylated protein. When O-GlcNAc binds to a target protein, it can inhibit phosphorylation, thereby modulating its function. Protein binding to O-GlcNAc is mediated by OGT, and meningioma expressed antigen 5 (MGEA5) is responsible for removing O-GlcNAc from the protein.

[0009] The present inventors conducted research based on the fact that proteins involved in cell damage and death caused by radiation are mainly regulated in activity by phosphorylation, and completed the present invention by confirming that salivary gland cell death caused by radiation was suppressed when an MGEA5 inhibitor was treated.

[0010]

[0011] [Prior Art Literature]

[0012] [Patent Document]

[0013] (Patent Document 1) Korean Patent Publication No. 10-2024-0049295

[0014]

[0015] The present invention aims to provide a composition for protecting salivary glands from radiation-induced damage.

[0016] The present invention aims to provide a method for protecting salivary glands from radiation-induced damage.

[0017]

[0018] 1. A composition for protecting salivary glands from radiation-induced damage, comprising an MGEA5 inhibitor.

[0019] 2. A composition for protecting radiation-induced salivary gland damage, wherein in the above 1, the MGEA5 inhibitor is any one selected from the group consisting of gRNA, siRNA, shRNA, dsRNA, miRNA, antisense nucleic acid, peptide, protein, aptamer, and compound.

[0020] 3. A composition for protecting radiation-induced salivary gland damage, wherein the MGEA5 inhibitor comprises a Cas9 protein and a gRNA having a nucleotide sequence of SEQ ID NO: 1 or 2.

[0021] 4. In the above 1, the MGEA5 inhibitor is a composition for protecting against radiation-induced salivary gland damage, which is any one of the compounds of chemical formulas 1 to 4, or a pharmaceutically acceptable salt or solvate thereof:

[0022] [Chemical Formula 1]

[0023]

[0024] [Chemical Formula 2]

[0025]

[0026] [Chemical Formula 3]

[0027]

[0028] [Chemical Formula 4]

[0029] .

[0030] 5. A composition for protecting salivary gland damage induced by radiation, wherein the radiation is irradiated at a dose of 1 Gy or more in the above 1.

[0031] 6. A composition for protecting radiation-induced salivary gland damage, wherein in the above 1, the salivary gland is any one selected from the group consisting of the submandibular gland, sublingual gland, and minor salivary gland.

[0032] 7. A composition for protecting the salivary gland from radiation-induced damage, used before radiation irradiation for the treatment of any one head and neck cancer selected from the group consisting of oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, glottic cancer, supraglottic cancer, subglottic cancer, nasal cancer, paranasal sinus cancer, salivary gland cancer, thyroid cancer, adenocarcinoma, mucoepidermoid carcinoma, sarcoma, lymphoma, and melanoma in the above 1.

[0033] 8. A method for protecting against radiation-induced salivary gland damage, comprising administering to an animal other than a human a composition of any one of the above 1 to 7.

[0034] 9. A method for protecting salivary glands from radiation-induced damage, further comprising the step of irradiating an animal with radiation in the above 8.

[0035]

[0036] The composition and method for protecting salivary gland damage induced by radiation of the present invention contain an MGEA5 inhibitor and can exhibit an effect of preventing, treating or improving salivary gland damage induced by radiation.

[0037]

[0038] Figure 1 shows the results of hematoxylin and eosin (H&E) staining, Masson's trichrome (MT) staining, and periodic acid-Schiff (PAS) staining of the submandibular glands of MGEA5 gene Wild-type (WT, + / +), Hetero (Het, + / -), and Knockout (KO, - / -) mice.

[0039] Figure 2 shows the extent of cell death by treating MGEA5 expression-inhibited cell models with various concentrations of hydrogen peroxide (H2O2). Figure 2A shows the results of a CCK-8 assay, Figure 2B shows the results of staining using MitoSox, and Figure 2C shows the results of confirming cell damage markers using Western blot.

[0040] Figure 3 shows the results of confirming the branching pattern of the submandibular gland by irradiating the embryonic salivary gland in vitro culture model after treating it with Thiamet G (Figure 3a) and counting epithelial buds (Figure 3b).

[0041] Figure 4 shows the results of immunofluorescence staining of eSMG with various antibodies.

[0042] Figure 5 shows the results of confirming the effect of radiation-induced HSG cell death inhibition in a cell model with suppressed MGEA5 expression. Figure 5A shows the colony forming assay performed after staining colonies with a 1% crystal violet solution, and Figure 5B is a graph quantifying the results of the colony forming assay.

[0043]

[0044] Hereinafter, the present invention will be described in detail.

[0045] The present invention relates to a composition for protecting salivary glands from radiation-induced damage, comprising an MGEA5 inhibitor.

[0046] In the present invention, the MGEA5 inhibitor may be at least one selected from the group consisting of RNA, siRNA, shRNA, dsRNA, miRNA, antisense nucleic acid, peptide, protein, aptamer, and compound, but is not limited thereto.

[0047] In the present invention, the protein also includes an antibody.

[0048] In one embodiment, the MGEA5 inhibitor comprises a Cas9 protein and a gRNA having a nucleotide sequence of SEQ ID NO: 1 or 2 (Table 1).

[0049] Sequence number gRNA sequence 15'-UGAGGACUCCUUUUAACCGU-3' 25'-CCUUUGGGUCCAUGCUCGUA-3'

[0050] In the present invention, gRNA is expressed from the oligonucleotide sequence of Table 2 when a plasmid for CRISPR-mediated silencing of MGEA5 is introduced into a cell.

[0051] In the present invention, the MGEA5 inhibitor may include, but is not limited to, any one of the compounds of formulae 1 to 4, a pharmaceutically acceptable salt or solvate thereof.

[0052] [Chemical Formula 1]

[0053]

[0054] [Chemical Formula 2]

[0055]

[0056] [Chemical Formula 3]

[0057]

[0058] [Chemical Formula 4]

[0059]

[0060]

[0061] In the present invention, the MGEA5 inhibitor may be, for example, thiamet G, MK-8719, ASN90 (ASN120290 or ASN-561), LY3372689, etc.

[0062] In one embodiment, the MGEA5 inhibitor is thiamet G.

[0063] “Compound” can be manufactured using common knowledge known in the field of organic chemistry or can be purchased and used as a commercially available compound.

[0064] “Pharmaceutically acceptable salts or solvates thereof” can be appropriately prepared or selected by a person skilled in the art of organic chemistry using knowledge known in the art.

[0065] In the present invention, the composition may be treated before or after radiation exposure.

[0066] The term “protection” means defense, prevention, prevention, blocking, alleviation, mitigation, suppression, treatment, etc.

[0067] “Radiation-induced damage” means any biological damage caused by radiation exposure.

[0068] “Radiation-induced damage” includes damage to the salivary glands due to radiation exposure.

[0069] In the present invention, “salivary gland” may be any one selected from the group consisting of the submandibular gland, sublingual gland, and minor salivary gland, but is not limited thereto.

[0070] In the present invention, radiation therapy for cancer that can cause salivary gland damage may be radiation therapy for head and neck cancer.

[0071] Head and neck cancer may be any one selected from the group consisting of oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, glottic cancer, supraglottic cancer, subglottic cancer, nasal cancer, paranasal sinus cancer, salivary gland cancer, thyroid cancer, adenocarcinoma, mucoepidermoid carcinoma, sarcoma, lymphoma, and melanoma, but is not limited thereto.

[0072] In the present invention, the radiation may be high dose or low dose.

[0073] “Radiation” may include, for example, X-rays, ultraviolet rays, electromagnetic radiation including alpha particles and gamma rays, or alpha or beta particles.

[0074] The term “Gy (gray)” refers to the dose of radiation capable of emitted 1 joule from 1 kg of biological tissue.

[0075] In the present invention, radiation may be irradiated at a dose of 1 Gy or more.

[0076] In the present invention, the radiation may be 1 to 3 Gy, 1 to 5 Gy, 1 to 10 Gy, 1 to 20 Gy, 1 to 30 Gy, 1 to 40 Gy, 1 to 50 Gy.

[0077] If the composition of the present invention is a pharmaceutical composition, it may be formulated into a conventional pharmaceutical formulation known in the art. Such pharmaceutical formulations include, but are not limited to, oral administration formulations, injections, suppositories, transdermal administration formulations, and nasal administration formulations.

[0078] The composition of the present invention can be appropriately administered to an individual according to a conventional method or administration route used in the art, depending on the purpose or need, and preferably, the drug can be noninvasively injected through a salivary gland duct in the oral cavity.

[0079] When formulating the composition of the present invention into an injection, it can be prepared according to conventional injection manufacturing methods known in the art. The injection may be dispersed in a sterile medium so that it can be administered directly to a patient, or it may be dispersed in an appropriate concentration by adding distilled water for injection before administration.

[0080] Oral dosage forms may be prepared, for example, as liquids, suspensions, powders, granules, tablets, capsules, pills, or extracts.

[0081] When formulated into each dosage form, a pharmaceutically acceptable carrier may be included in addition to the active ingredient, the MGEA5 inhibitor.

[0082] Pharmaceutically acceptable carriers are those commonly used in drug formulations and may include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.

[0083] In addition, the pharmaceutical composition may further include fillers, bulking agents, binders, lubricants, wetting agents, disintegrating agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, fragrances, preservatives, etc. as additives and auxiliary agents.

[0084] The content of the MGEA5 inhibitor in the composition is a pharmaceutically effective amount.

[0085] A pharmaceutically effective amount is an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level can be determined based on the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the excretion rate, the duration of treatment, concomitant drugs used, and other factors well known in the medical field.

[0086] The composition of the present invention may be administered alone or in combination. It may be administered sequentially or simultaneously with other protective, emollient, or therapeutic agents. Single or multiple administrations are possible. The dosage is preferably the amount that achieves maximum effect with the minimum amount without causing side effects. This can be appropriately determined by those skilled in the art.

[0087] The effective dose of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, the absorption, inactivation rate, and excretion rate of the active ingredient in the body, the type of disease, and concomitant medication. For example, 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight, may be administered daily or every other day, or divided into 1 to 3 doses per day. The dose may increase or decrease depending on the route of administration, severity of obesity, sex, weight, age, etc.

[0088] The present invention provides a method for protecting against radiation-induced salivary gland damage comprising administering to an animal a composition comprising an MGEA5 inhibitor.

[0089] The method for protecting salivary gland damage induced by radiation of the present invention may further include a step of irradiating an animal with radiation.

[0090] The description of the “composition for protecting against radiation-induced salivary gland damage” of the present invention can be applied as is to the above “method for protecting against radiation-induced salivary gland damage.”

[0091] The above animal may be any mammal, including, but not limited to, humans, livestock and pets.

[0092] The above animal may be an animal requiring administration of a composition comprising an MGEA5 inhibitor.

[0093] The above animals may be animals at risk for radiation-induced salivary gland damage.

[0094] Hereinafter, the present invention will be described in more detail with examples.

[0095]

[0096] Example

[0097] Experimental materials and methods

[0098] 1.1. Plasmid constructs

[0099] To construct a plasmid for CRISPR-mediated silencing of MGEA5, the lentiCRISPRv2 vector (Addgene, Plasmid #52961) was used as a backbone. For genetic perturbation of MGEA5 in HSG cells, complementary oligonucleotide pairs were phosphorylated with T4 PNK (NEB M0201S) at 37°C for 30 min, incubated at 95°C for 5 min, and then gradually cooled to 25°C at a rate of 5°C / min until annealing was complete. The annealed oligonucleotide pairs were ligated to the digested lentiCRISPRv2 plasmid. The specific sequences of the oligonucleotides used are shown in Table 2.

[0100]

[0101] Sequence number Oligonucleotide sequence 35'-CACCGTGAGGACTCCTTTTAACCGT-3'45'-AAACACGGTTAAAAGGAGTCCTCAC-3'55'-CACCGCCTTTGGGTCCATGCTCGTA-3'65'-AAACTACGAGCATGGACCCAAAGGC-3'

[0102]

[0103] 1.2. Creation of stable cells

[0104] To generate MGEA5-deficient HSG cells, the plasmid for CRISPR-mediated silencing of MGEA5 constructed above was introduced into cells using Lipofectamine 3000 (Thermo Fisher Scientific). After 2 days, selection with 2 μg / ml puromycin was initiated. Puromycin-resistant HSG cells were maintained in DMEM (HyClone) supplemented with 10% fetal bovine serum (FBS) (Gibco), 1% penicillin-streptomycin, and 2 μg / ml puromycin.

[0105]

[0106] 1.3. Cell survival assay

[0107] For cell viability analysis, control and MGEA5-deficient cells were seeded at 8,000 cells / well in 96-well plates. After treatment with the indicated concentrations of H2O2 for 24 h, 10 μl of CCK-8 solution (D-Plus™ CCK, Dong-In LS) was added to each well, and the absorbance at 450 nm was measured 1 h later using a microplate reader.

[0108]

[0109] 1.4. Immunoblot analysis

[0110] Cells were directly disrupted in Laemmli buffer [60 mM Tris-HCl (pH 6.8), 2% (w / v) sodium dodecyl sulfate (SDS), 10% (v / v) glycerol, and 0.02% (w / v) bromophenol blue)], followed by sonication and heat denaturation. Samples were separated on a 12% SDS-polyacrylamide gel, and proteins were transferred to polyvinylidene fluoride membranes. After blocking with 5% skimmed milk for 30 min at room temperature, the membranes were incubated overnight at 4°C with the following primary antibodies: anti-γH2AX (Bethyl Laboratories), anti-SOD2 (Cusabio), anti-MGEA5 (Abcam), anti-GAPDH (Santa Cruz biotechnology), and anti-O-GlcNAc (Thermo Fisher Scientific). The following day, the membrane was incubated with horseradish peroxidase-conjugated secondary anti-rabbit (Abcam) and anti-mouse (Bethyl Laboratories) antibodies for 1 h at room temperature. Immunoreactive signals were detected using the D-Plus™ ECL Femto system (Dong-In LS).

[0111]

[0112] Experimental Example 1. Analysis of changes in salivary gland structure according to MGEA5 expression level.

[0113] We examined whether reducing MGEA5 expression in mice affected salivary gland structure. To this end, we either knocked out the MGEA5 gene in mice or treated them with the MGEA5 inhibitor thiamet G to inhibit gene function. Submandibular glands were then stained. No structural abnormalities were observed in response to MGEA5 expression levels (Fig. 1).

[0114]

[0115] Experimental Example 2. Confirmation of the inhibitory effect on HSG cell death caused by oxidative stress in a cell model with suppressed MGEA5 expression.

[0116] To induce intracellular oxidative stress similar to that induced by radiation in a cell model with suppressed MGEA5 expression, hydrogen peroxide (H2O2) was administered at various concentrations to determine whether cell death occurred.

[0117] When 8,000 control and MGEA5 KO HSG (human salivary gland cell line, culture medium: DMEM with 10% FBS and 1% penicillin-streptomycin) cells were seeded and cell viability was observed using a CCK-8 assay after 24 hours through a H2O2 concentration gradient, it was confirmed that the viability of MGEA5 KO HSG cells was statistically significantly increased compared to the control HSG up to H2O2 250 μM (Fig. 2A).

[0118] When oxidative stress inside mitochondria was visualized using MitoSox, it was confirmed that mitochondrial oxidative stress was reduced in MGEA5 KO HSGs when treated with 200 μM H2O2 compared to control HSGs (Fig. 2B).

[0119] Markers of cellular damage due to oxidative stress were observed using Western blot. As the H2O2 concentration increased, the expression of gamma-H2AX, a marker of DNA double-strand breakage, increased, but this was decreased in MGEA5 KO HSG cells. In addition, the expression of the antioxidant protein SOD2 was increased in MGEA5 KO HSG cells (Fig. 2C).

[0120] Through the above experiment, it was confirmed that cell death was suppressed in MGEA5 gene-deficient cells.

[0121]

[0122] Example 1. Confirmation of the effect of Thiamet G (TG) treatment on the inhibition of salivary gland damage caused by radiation.

[0123] The effects on salivary gland cells were observed by treating an embryonic salivary gland in vitro culture model with TG, an MGEA5 inhibitor, and then irradiating the cells.

[0124] Embryonic submandibular glands (eSMG) were collected from pregnant female ICR mice on embryonic day 13.5 and placed on polycarbonate membranes (Watman, 110405) suspended in 200 μL of culture medium (DMEM / F12 1:1 (Gibco, Grand Island, NY) supplemented with 150 μg / mL ascorbic acid (Sigma-Aldrich, A5960), 50 μg / mL transferrin (Sigma-Aldrich, T8158), and 1% v / v penicillin-streptomycin (Gibco, 15140122)) and cultured at the air-media interface. After collection and placement on the polycarbonate membrane, the eSMGs were stabilized for 2 h and treated with 2, 20, and 100 μM TG, followed by treatment with cesium-137 radiation 24 h later.

[0125] In the TG-untreated group, 5 Gy of radiation induced cell death in c-kit+ progenitor cells (c-kit) and parasympathetic ganglia (TUJ1), but radiation-induced cell death was inhibited by treatment with 100 μM TG.

[0126] Epithelial bud counting showed that the group pretreated with TG at a concentration of 20 μM or higher showed an excellent radioprotective effect, and TG treatment at a concentration of 100 μM had no effect on the branching pattern of the submandibular gland (Fig. 3).

[0127] Next, eSMG was observed by immunofluorescence staining with various antibodies. The expression of c-kit, a progenitor cell marker for salivary gland regeneration, was significantly improved in the group treated with TG 20 μM or more, and progenitor cell apoptosis (cleaved caspase 3) was also reduced. The innervation of the parasympathetic nerve (PSG) is important for the regeneration and smooth function of the salivary gland, and the branching (branch part of TUJ1) and cell body (columnar part of TUJ1) of the PSG were reduced in the TG-untreated group, but were improved in the group treated with TG 20 μM or more. When the cell body of the PSG was enlarged, apoptosis (cas3, green) of the cell body was reduced in the group treated with TG 20 μM or more (Fig. 4).

[0128] The above experiment confirmed that inhibition of MGEA5 suppressed radiation-induced salivary gland damage.

[0129]

[0130] Example 2. Confirmation of the effect of suppressing MGEA5 expression on radiation-induced salivary gland damage.

[0131] We irradiated a cell model with suppressed MGEA5 expression and confirmed the effect on HSG (Human salivary gland cell line) cells.

[0132] HSG cells were seeded at low density, treated with radiation doses, and colonies were stained with a 1% crystal violet solution, after which a colony forming assay was performed. As a result, the number of colonies decreased as the radiation dose increased, but the decrease was less in MGEA5 KO HSG (Fig. 5).

[0133] The above experiment showed that MGEA5 gene deficiency suppresses cell death induced by radiation.

Claims

1. A composition for protecting salivary glands from radiation-induced damage, comprising an MGEA5 inhibitor.

2. A composition for protecting radiation-induced salivary gland damage according to claim 1, wherein the MGEA5 inhibitor is any one selected from the group consisting of gRNA, siRNA, shRNA, dsRNA, miRNA, antisense nucleic acid, peptide, protein, aptamer, and compound.

3. A composition for protecting radiation-induced salivary gland damage according to claim 1, wherein the MGEA5 inhibitor comprises a Cas9 protein and a gRNA having a nucleotide sequence of SEQ ID NO: 1 or 2.

4. In claim 1, the MGEA5 inhibitor is a composition for protecting radiation-induced salivary gland damage, which is any one of the compounds of formulae 1 to 4, or a pharmaceutically acceptable salt or solvate thereof: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] 5. A composition for protecting salivary gland damage induced by radiation, wherein the radiation is irradiated at a dose of 1 Gy or more according to claim 1.

6. A composition for protecting radiation-induced salivary gland damage, wherein the salivary gland in claim 1 is any one selected from the group consisting of the submandibular gland, sublingual gland, and minor salivary gland.

7. A composition for protecting the salivary glands from radiation-induced damage, which is used before radiation irradiation for the treatment of any one head and neck cancer selected from the group consisting of oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, glottic cancer, supraglottic cancer, subglottic cancer, nasal cancer, paranasal sinus cancer, salivary gland cancer, thyroid cancer, adenocarcinoma, mucoepidermoid carcinoma, sarcoma, lymphoma, and melanoma, in claim 1.

8. A method for protecting against radiation-induced salivary gland damage, comprising administering to an animal other than a human a composition of any one of claims 1 to 7.

9. A method for protecting a radiation-induced salivary gland from damage, further comprising the step of irradiating the animal with radiation according to claim 8.

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