Pharmaceutical composition for preventing or treating depression- or anxiety-related diseases, comprising lazertinib or pharmaceutically acceptable salt thereof

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating depression- or anxiety-related diseases, comprising lazertinib or a pharmaceutically acceptable salt thereof. Lazertinib of the present invention alleviates symptoms of depression and anxiety by inhibiting 5-HTT, and thus the composition according to the present invention can be effectively used for preventing and treating depression or anxiety-related diseases.

Description

Pharmaceutical composition for preventing or treating depression or anxiety-related diseases comprising LAZERTINIB or a pharmaceutically acceptable salt thereof

[0001] The present invention relates to a pharmaceutical composition for preventing or treating a disease related to depression or anxiety, and more preferably, to a pharmaceutical composition for preventing or treating a disease related to depression or anxiety, comprising Lazertinib or a pharmaceutically acceptable salt thereof.

[0002] Depression is a serious illness characterized by persistent low mood, loss of excitement or interest in daily life, sleep problems, fatigue, severe difficulties fulfilling social and occupational roles, and even suicidal thoughts. Biochemical, genetic, and environmental factors are known to contribute to its cause. Treatment options include consultation with a specialist, behavioral therapy, and medication. Current medications include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin-norepinephrine reuptake inhibitors (SNRIs).

[0003] 5-HTT (SLC6A4), known as a major target, is responsible for the reuptake of serotonin in neurons in the brain, and recent studies have suggested that epigenetic regulation of SLC6A4 expression by DNA methylation or histone acetylation contributes to major depressive disorder (MDD) or depression. In particular, abnormal expression and activity of SLC6A4 promotes the reuptake of serotonin in the brain, resulting in a decrease in the amount of serotonin. Based on this mechanism, antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) were developed. However, there is a high possibility of relapse and side effects such as anorexia, insomnia, nervousness, headache, and withdrawal symptoms upon discontinuation, so new treatments are needed.

[0004] Meanwhile, Lazertinib is a drug approved as a first-line treatment for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).

[0005] The present inventors utilized DeepMatcher (DMC), an AI drug discovery platform, to identify the 5-HT transporter (5-HTT) as a novel target of lazertinib. Through in vitro and in vivo tests, they confirmed that lazertinib effectively inhibits 5-HTT. 5-HTT is known to be an important target for the treatment of depression and anxiety, and the inhibitory effects of lazertinib on depression and anxiety were confirmed through the development of a zebrafish model. Therefore, the composition according to the present invention is expected to be useful as a pharmaceutical composition for the prevention or treatment of diseases related to depression or anxiety.

[0006] The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating a disease related to depression or anxiety, comprising Lazertinib or a pharmaceutically acceptable salt thereof.

[0007] An object of the present invention is to provide a method for preventing or treating a disorder related to depression or anxiety, comprising administering a therapeutically effective amount of Lazertinib or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0008] An object of the present invention is to provide a use of the present invention's lazertinib or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating a disease related to depression or anxiety.

[0009] An object of the present invention is to provide a composition comprising lazertinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of depression or anxiety-related disorders.

[0010] The present invention provides a pharmaceutical composition for preventing or treating a disease related to depression or anxiety, comprising lasertinib or a pharmaceutically acceptable salt thereof.

[0011] In the present invention, lasertinib has a structure represented by the following chemical formula 1.

[0012] [Chemical Formula 1]

[0013]

[0014] The above-mentioned lazertinib is a targeted anticancer drug developed for the treatment of non-small cell lung cancer with specific genetic mutations, and is known to be an effective treatment option, particularly for patients with EGFR (epidermal growth factor receptor) mutation-positive non-small cell lung cancer.

[0015] In one embodiment of the present invention, it was confirmed that Lazertinib can inhibit 5-HTT (5-HT transporter) in addition to EGFR, and this can be used to alleviate symptoms of depression or anxiety-related disorders and exhibit therapeutic effects. In other words, Lazertinib exhibits excellent preventive, therapeutic, or ameliorating effects against depression or anxiety-related disorders.

[0016] The term "depression" as used in the present invention mainly refers to a neuropsychiatric disorder that feels sadness, dullness, loss of emotion, anhedonia (lack of pleasure), grief, agitation, or retardation, guilt and worthlessness thoughts and feelings, and in severe cases, commits acts such as suicide, hallucinations, and delusions. Specifically, a depression-related disease is a concept that includes symptoms that cause cognitive, mental, and physical symptoms due to loss of motivation and persistent depression, resulting in a decline in daily functioning, and refers to a depression-related disease related to the above symptoms, including persistent depression, decreased motivation, sleep disorders such as insomnia, weight changes related to decreased or increased appetite, recurrent thoughts or attempts of suicide, negative thinking, and excessive guilt. Examples may include major depressive disorder, persistent depressive disorder, bipolar disorder, treatment-resistant depression (TRD), postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder.

[0017] Specifically, in the present invention, “depression” follows the definition of “Major Depressive Disorder (MDD)” by the U.S. Food and Drug Administration (FDA), which follows the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition). According to the criteria, depression is classified as a mood disorder, and at least five of the nine symptoms listed below persist for more than two weeks, must include “depressed mood” or “decreased interest / pleasure,” and the symptoms impair social and occupational functioning, and cannot be explained by medication or other medical conditions.

[0018] 1. Depressed mood that lasts almost every day

[0019] 2. Decreased interest / pleasure in almost all activities

[0020] 3. Weight changes (gain or loss) or changes in appetite

[0021] 4. Insomnia or hypersomnia

[0022] 5. Psychomotor agitation or retardation

[0023] 6. Fatigue or decreased energy

[0024] 7. Feelings of worthlessness or excessive guilt

[0025] 8. Difficulty concentrating or indecisiveness

[0026] 9. Suicidal thoughts or attempts

[0027] The term "anxiety disorder" as used herein refers to a neuropsychiatric disorder that exhibits physical or behavioral symptoms such as headache, increased heart rate, increased breathing rate, gastrointestinal symptoms, panic disorder, cold sweat, fear, and sweating due to vague feelings of discomfort and anxiety. Specifically, anxiety-related diseases include panic disorder (with or without agoraphobia), specific phobias (e.g., fear of heights, fear of blood, fear of snakes), social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and acute stress disorder.

[0028] Specifically, in the present invention, “anxiety disorder” is defined as a mental illness in which chronic and excessive anxiety and worry interfere with daily life, as defined by the U.S. Food and Drug Administration (FDA), and is classified as follows considering the following DSM-5 categories, and means a case in which the following symptoms persist for more than 6 months, the symptoms interfere with social and occupational functions, and cannot be explained by medication or other medical conditions.

[0029] 1. Generalized Anxiety Disorder (GAD): Excessive anxiety and worry, tension, restlessness, fatigue, difficulty concentrating, muscle tension, and sleep disturbance lasting more than 6 months.

[0030] 2. Panic Disorder: Sudden, recurrent panic attacks, including physical symptoms such as heart palpitations, sweating, shortness of breath, dizziness, and fear of dying.

[0031] 3. Social Anxiety Disorder (SAD): Excessive anxiety and avoidance in social situations, which severely affects interpersonal relationships and social activities.

[0032] 4. Specific Phobia: Extreme fear of a specific object (e.g. spiders, heights, airplanes) and strong anxiety response when exposed to the object of fear.

[0033] 5. Separation Anxiety Disorder: This disorder mainly affects children and adults and is characterized by extreme anxiety about separation from important people.

[0034] 6. Selective Mutism: A disorder in which a person does not speak in certain situations (mainly occurs in children)

[0035] According to one embodiment of the present invention, lazertinib is a serotonin reuptake inhibitor that blocks the reuptake of serotonin, a key neurotransmitter, thereby increasing serotonin concentration within synapses, thereby inducing therapeutic effects for depression and anxiety disorders. Currently, representative serotonin reuptake inhibitors, such as fluoxetine, sertraline, and paroxetine, are FDA-approved drugs, and in this process, 5-HTT inhibitors have been repeatedly proven effective in treating panic disorder and generalized anxiety disorder. Specifically, the present invention's Lazertinib can inhibit 5-HTT (5-HT transporter), and as the inhibitory effect on depression and anxiety was confirmed through a zebrafish model, it was confirmed that it can be usefully used for the improvement and treatment of related diseases such as depression or anxiety. Recently, Lazertinib was approved as a first-line treatment for non-small cell lung cancer in combination with Librivant in August 2024, and as such, it is expected to be effective in expanding combination therapy for depression accompanying cancer treatment in addition to the treatment of depression and anxiety.

[0036] The term “prevention” as used in the present invention means any act of suppressing or delaying the onset of a depression or anxiety-related disease by administering a composition.

[0037] The term “treatment” used in the present invention means any action by which the symptoms of the disease are improved or beneficially changed by administration of the composition.

[0038] In the present invention, “pharmaceutically acceptable salt” means a salt commonly used in the pharmaceutical industry, and for example, inorganic ionic salts manufactured with calcium, potassium, sodium, and magnesium, etc.; inorganic acid salts manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, and sulfuric acid, etc.; organic acid salts manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid, etc.; sulfonic acid salts manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid, etc. Amino acid salts made from glycine, arginine, lysine, etc.; and amine salts made from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; however, the types of salts meant in the present invention are not limited by these listed salts.

[0039] In addition, the lasertinib of the present invention includes not only pharmaceutically acceptable salts but also all salts, hydrates, and solvates that can be prepared by conventional methods.

[0040] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, and may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.

[0041] The pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical composition of the present invention may include, but is not limited to, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, and other pharmaceutically acceptable additives.

[0042] When the pharmaceutical composition of the present invention is formulated as an oral solid preparation, it includes tablets, pills, powders, granules, capsules, etc., and such solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., and include, but are not limited to, lubricants such as magnesium stearate and talc.

[0043] When the pharmaceutical composition of the present invention is formulated as an oral liquid, it includes a suspension, a solution, an emulsion, a syrup, etc., and includes, but is not limited to, a diluent such as water or liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, etc.

[0044] When the pharmaceutical composition of the present invention is formulated for parenteral use, it includes a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository. Non-aqueous solvents and suspensions include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for a suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, and the like can be used, but are not limited to these.

[0045] The composition may be administered in single or multiple doses in a pharmaceutically effective amount. The term “pharmaceutically effective amount” as used herein means an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prevention or treatment, and the effective dosage level may be determined according to factors including the severity of the disease, the activity of the drug, the patient’s age, weight, health, sex, the patient’s sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, drugs used in combination or concurrently with the composition of the present invention used, and other factors well known in the medical field. For example, lazertinib or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg / kg per day, and the administration may be administered once a day or in several divided doses.

[0046] The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans via various routes, including, but not limited to, oral administration, intrathecal, intra-auricular, intraperitoneal, intravenous, intramuscular, subcutaneous, intrauterine, sublingual, or intracerebrovascular injection. In addition, it can be applied directly to the affected area as needed.

[0047] The pharmaceutical composition of the present invention may contain 0.01 to 95 wt%, preferably 1 to 80 wt%, of Lazertinib or a pharmaceutically acceptable salt thereof based on the total weight of the composition.

[0048] The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. Furthermore, the pharmaceutical composition of the present invention can be administered singly or in multiple doses. Taking all of the above factors into consideration, it is important to administer the amount that achieves maximum efficacy with the minimum amount possible without causing side effects, a determination readily made by those skilled in the art.

[0049] The term "subject" of the present invention encompasses an animal or human whose symptoms can be improved by administration of a pharmaceutical composition according to the present invention. By administering a therapeutic composition according to the present invention to a subject, depression or anxiety-related disorders can be effectively prevented and treated.

[0050] The term "administration" in the present invention refers to introducing a given substance into a human or animal by any suitable method. The therapeutic composition according to the present invention may be administered orally or parenterally via any conventional route, as long as it can reach the target tissue. Furthermore, the therapeutic composition according to the present invention may be administered by any device capable of transporting the active ingredient to target cells.

[0051] Another aspect of the present invention provides a method for preventing or treating a disorder related to depression or anxiety, comprising administering a therapeutically effective amount of Lazertinib or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0052] In the present invention, the term “lasertinib” or “depression or anxiety-related disease” is as described above.

[0053] The term “subject” of the present invention refers to any animal that exhibits or may exhibit a depression or anxiety-related disorder, and typically may be an animal that may exhibit a beneficial effect from treatment with the Lazertinib of the present invention or a pharmaceutically acceptable salt thereof, but includes, without limitation, any subject that has or is likely to have a depression or anxiety-related disorder. As described above, by administering the pharmaceutical composition of the present invention to a subject, the depression or anxiety-related disorder can be effectively prevented or treated.

[0054] Another aspect of the present invention provides a use of the present invention's lazertinib or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating a depression or anxiety related disorder.

[0055] Another aspect of the present invention provides a composition comprising lazertinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a depression or anxiety-related disorder.

[0056] The present invention provides a food composition for preventing or improving a disease related to depression or anxiety, comprising lasertinib or a food-based acceptable salt thereof.

[0057] The term “improvement” of the present invention means any act of improving or beneficially changing a depression or anxiety-related disease by administering the composition of the present invention.

[0058] In the food composition of the present invention, the lasertinib and its salt are preferably included in an amount of 0.00001 to 0.01 wt% relative to the food composition. If the amount is less than 0.00001 wt%, the effect is minimal, and if the amount exceeds 0.01 wt%, the increase in effect relative to the amount used is minimal, making it uneconomical.

[0059] Food-grade acceptable salt may be applied in the same manner as pharmaceutically acceptable salt.

[0060] When the food composition of the present invention is used as a food additive, it can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method.

[0061] In the present invention, the food composition includes a health functional food.

[0062] The above “health functional food” refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body as defined in Act No. 6727 on Health Functional Foods, and “functionality” refers to consumption for the purpose of obtaining a useful effect for health purposes such as regulating nutrients for the structure and function of the human body or physiological effects.

[0063] The food composition and health functional food of the present invention may include additional ingredients. For example, they may include biotin, folate, pantothenic acid, vitamins A, C, D, E, B1, B2, B6, B12, niacin, etc. In addition, they may include minerals such as chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), zinc (Zn), iron (Fe), and calcium (Ca). In addition, they may include amino acids such as cysteine, valine, lysine, and tryptophan. In addition, food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), coloring agents (tar color, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), bactericides (bleaching powder and high-purity bleaching powder, sodium hypochlorite, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), reinforcing agents, emulsifiers, thickeners (pasting agents), film-forming agents, antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), seasonings (MSG, monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), gum bases, antifoaming agents, solvents, and improvers can be added. The above additives can be selected depending on the type of food and used in an appropriate amount.

[0064] Since the lazertinib of the present invention alleviates symptoms of depression and anxiety by inhibiting 5-HTT, the composition according to the present invention can be usefully used for the prevention and treatment of diseases related to depression or anxiety.

[0065] Figure 1 is a graph evaluating the binding affinity of Lazertinib to human 5-HTT (5-HT transporter).

[0066] Figure 2 is a graph evaluating the antidepressant and anti-anxiety effects of lazertinib using a zebrafish model.

[0067] Figure 3 is a drawing showing the movement of a zebrafish in each circle based on the results of Figure 2 above.

[0068] Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention and the scope of the present invention is not limited to these examples.

[0069] <Example>

[0070] Example 1. Evaluation of the binding affinity of lazertinib to human 5-HTT (5-HT transporter) (In VitroEfficacy)

[0071] To evaluate the binding affinity of Lazertinib to human 5-HT transporter, various concentrations of STB-CRPS8724 (Lazertinib) were added to a reaction solution containing human 5-HT transporter and radioligand, and the mixture was allowed to react for a certain period of time to reach equilibrium. Afterwards, the bound radioligand and the free radioligand were separated through membrane filtration or centrifugation, and the amount of bound radioligand was measured to evaluate the degree of binding inhibition of Lazertinib (STB-CRPS8724), and the results are shown in Fig. 1.

[0072] IC based on binding inhibition data 50 The value was calculated. IC 50 The values ​​represent the concentration of STB-CRPS8724 that inhibits the binding of the radioligand by 50%. Also, K i The value represents the affinity with which the drug (STB-CRPS8724, Lazertinib) binds to the target protein (human 5-HTT). A lower Ki value means that the drug binds more strongly to the target protein.

[0073] Therefore, Lazertinib exhibited high binding affinity for human 5-HTT (h). Specifically, IC 50The value was 23 nM (2.3E-08 M), showing that lazertinib effectively binds to 5-HTT and inhibits the binding of the radioligand even at low concentrations. Also, K i The value was 11 nM (1.1E-08 M), indicating that lazertinib has a very high binding affinity for 5-HTT.

[0074] That is, the experimental results indicate that lazertinib acts as an antagonist against 5-HTT.

[0075]

[0076] Example 2. Evaluation of antidepressant and anti-anxiety effects using a zebrafish model (In Vivo Efficacy)

[0077] To confirm the antidepressant and anxiolytic effects of STB-CRPS8724 (Lazertinib) in vivo, zebrafish fry cultured for 5 days (dpf, day post-fertilization) after drug treatment were transferred one by one to 24 wells, and after a 5-minute light adaptation period, a sudden 10-minute dark illumination change was induced to confirm thigmotaxis, a behavior in which zebrafish feel anxious and move around the edge of the well. Fluoxetine (Sigma-Aldrich, PHR1394), used as a positive control (PC), was exposed at a concentration of 25 μM for 1 hour at 6 dpf. In addition, two test drugs (Drug C: Lazertinib, Drug D: Osimertinib) were dissolved in DMSO (Sigma-Aldrich, 276855) to prepare a 100 mM stock, and exposed for 1 hour at the final experimental concentration at 6 dpf. The effect of improving thigmotaxis behavior is shown in Figure 2, and Figure 3 shows the movement patterns of zebrafish in each circled area.

[0078] According to Fig. 2, the time that zebrafish stayed at the edge of the well and the distance moved were measured for 10 minutes to evaluate thigmaotaxis, which represents depressive and anxious behaviors. As a result, the positive control group, fluoxetine, showed a statistically significant decrease (p < 0.05) in thigmotaxis behavior of zebrafish when treated with 25 μM fluoxetine, and STB-CRPS8724 (Drug C, Lazertinib) also showed a statistically significant decrease (p < 0.05) in thigmotaxis behavior of zebrafish. However, when osimertinib (Drug D) was treated, no decrease in thigmotaxis behavior was observed, and there was no statistical significance (p > 0.05).

[0079] Also, according to Figure 3, fluoxetine and lazertinib showed a lighter red color, while osimertinib showed a stronger red color. The stronger the red color, the more thigmaotaxis there was.

[0080] Therefore, lazertinib exhibited antidepressant and anxiolytic effects in a zebrafish model, improving thigmotaxis behavior at a level similar to that of fluoxetine. Furthermore, osimertinib did not exhibit antidepressant or anxiolytic effects in a zebrafish model.

[0081] That is, lazertinib has high binding affinity for 5-HTT and exhibits antidepressant and anti-anxiety effects through this mechanism of action.

Claims

1. A pharmaceutical composition for preventing or treating a disease related to depression or anxiety, comprising Lazertinib or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition according to claim 1, wherein the depression or anxiety-related disease is depression or anxiety.

3. A pharmaceutical composition according to claim 1, wherein the composition inhibits the activity of 5-HT transporter (5-HTT).

4. A pharmaceutical composition according to claim 1, wherein the disease is depression.

5. A food composition for preventing or improving a disease related to depression or anxiety, comprising Lazertinib or a pharmaceutically acceptable salt thereof.

6. A food composition according to claim 5, wherein the disease related to depression or anxiety is depression or anxiety.

7. A food composition according to claim 5, wherein the composition inhibits the activity of 5-HT transporter (5-HTT).

8. A food composition according to claim 5, wherein the disease is depression.

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