Application of EGFR (epidermal growth factor receptor) inhibitor medicine in preparation of anti-aging medicine

Abstract

The invention discloses application of an EGFR (epidermal growth factor receptor) inhibitor drug in preparation of an anti-aging drug, and belongs to the field of biological medicines. Specifically, the invention discloses osimertinib, moblog tinib and salt thereof, and moblog tinib succinate, which can obviously prolong the service life of caenorhabditis elegans; a further experiment proves that osimertinib and mobolotinib succinate can be used for remarkably improving the heat stress resistance, oxidative stress resistance, exercise ability and swallowing ability of caenorhabditis elegans; experimental results show that the osimertinib and the mobolotinib succinate have great potential and application prospects in the aspect of anti-aging.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the anti-aging activity and application of EGFR inhibitor drugs osimertinib, mobocictinib, and mobocictinib succinate. Background Technology

[0002] Today, due to increased life expectancy and declining birth rates, the world faces various economic and social challenges brought about by an aging population. The physical and mental health challenges of aging not only disrupt the lives of affected individuals but also place a heavy burden on their families and society. If effective means can be adopted to extend healthy lifespan and corresponding anti-aging interventions can be implemented for the elderly population, not only can life expectancy be further extended, but the physical health of the elderly can also be improved, reducing their dependence on others and society, and significantly improving the overall quality of life for humanity.

[0003] Numerous studies have focused on discovering drugs that can delay aging, and several bioactive molecules with anti-aging potential have been identified from synthetic compounds and natural products, such as metformin, rapamycin, nicotinamide mononucleotide (NMN), resveratrol, and quercetin. However, no drug with anti-aging as its primary therapeutic effect has yet been approved for marketing. Therefore, continued research into the discovery of anti-aging bioactive molecules is of great significance, providing new strategies for anti-aging research and related applications.

[0004] Mobocictinib, mobocictinib succinate, and osimertinib are all marketed drugs for the treatment of non-small cell lung cancer (NSCLC), and all are epidermal growth factor receptor (EGFR) inhibitors. Osimertinib is a third-generation EGFR inhibitor that targets and inhibits the kinase activity of the EGFR T790M mutation, and its selectivity is superior to that of second-generation EGFR inhibitors, making it one of the important drugs in the field of targeted therapy for NSCLC. Another common type of EGFR mutation in NSCLC is the exon 20 insertion mutation (ex20ins). First-, second-, and third-generation EGFR inhibitors have limited inhibitory effects on the kinase activity of this type of mutation. Mobocictinib and mobocictinib succinate are first-in-class drugs targeting the EGFR ex20ins mutation. They have shown good selectivity in preclinical studies and were approved by the FDA through the accelerated approval process in September 2021, becoming the first oral targeted therapy for patients with NSCLC carrying the EGFR ex20ins mutation. To date, research on mobocictinib, mobocictinib succinate, and osimertinib has mainly focused on their effects on non-small cell lung cancer, and there are no reports on their anti-aging activities. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing applications of osimertinib, mobocictinib, and mobocictinib succinate in anti-aging.

[0006] To achieve the above objectives, the present invention employs the following technical solution: The osimertinib, mobocictinib, and mobocictinib succinate described in this invention are FDA-approved drugs and are synthetic products.

[0007] The chemical structural formula of mobocetinib is shown in formula (Ⅰ): The chemical structural formula of mobocetinib succinate is shown in formula (II): The chemical structural formula of osimertinib is shown in formula (III): One or more pharmaceutically acceptable carriers may be added, and the drug may be formulated into one or more of the following dosage forms: tablets, pills, capsules, granules, microcapsule tablets, suspensions, drop pills, oral liquids, injections, aerosols, suppositories, and subcutaneous dosage forms.

[0008] Furthermore, the carrier comprises one or more of the following: calcium carbonate, calcium phosphate, calcium sulfate, sucrose, glucose, lactose, fructose, xylitol, sorbitol, starch, starch paste, cellulose derivatives, gelatin, polyvinylpyrrolidone, sodium chloride, dextrin, stearic acid, magnesium stearate, calcium stearate, vegetable oil, polyethylene glycol, sterile phosphate-buffered saline, saline, and Ringer's solution.

[0009] Furthermore, the oral dosage form includes solid oral dosage forms (such as enteric-coated tablets, pellets, oral tablets, chewable tablets, granules, powders or capsules) or liquid oral dosage forms (such as syrups or tinctures).

[0010] Furthermore, osimertinib, mobocetinib, and mobocetinib succinate can also be used in combination with other active pharmaceutical ingredients to prepare other new drug compositions.

[0011] Prior to this invention, osimertinib, mobocetinib, and mobocetinib succinate had not been found to have anti-aging activity; nor had there been any reports of using the above three compounds as raw materials to prepare pharmaceutical formulations for anti-aging purposes.

[0012] The beneficial effects of this invention are as follows: This invention is the first to discover that osimertinib, mobocictinib, and mobocictinib succinate possess significant anti-aging activity in experimental animals. Lifespan experiments conducted in the model organism *C. elegans* showed that osimertinib, mobocictinib, and mobocictinib succinate all significantly prolonged the lifespan of *C. elegans*; simultaneously, osimertinib and mobocictinib succinate significantly enhanced the antioxidant capacity and heat stress resistance of *C. elegans*; in terms of behavior, osimertinib and mobocictinib succinate significantly improved the motility and swallowing ability of *C. elegans*. It is evident that the above compounds possess significant anti-aging potential, and drugs prepared from them can be used to prolong healthy lifespan or delay aging. Attached Figure Description

[0013] Figure 1 A schematic diagram showing the experimental results of the effect of mobocetinib succinate on the lifespan of Caenorhabditis elegans. Figure 2 A schematic diagram showing the experimental results of the effect of mobocetinib on the lifespan of Caenorhabditis elegans; Figure 3 A schematic diagram showing the experimental results of the effect of osimertinib on the lifespan of Caenorhabditis elegans; Figure 4 A schematic diagram showing the experimental results of the effect of mobocetinib succinate on the heat stress resistance of Caenorhabditis elegans. Figure 5 A schematic diagram showing the experimental results of the effect of osimertinib on the heat stress resistance of Caenorhabditis elegans; Figure 6A schematic diagram showing the experimental results of the effect of mobocetinib succinate on the antioxidant stress capacity of Caenorhabditis elegans. Figure 7 A schematic diagram showing the experimental results of the effect of osimertinib on the oxidative stress resistance of Caenorhabditis elegans; Figure 8 A schematic diagram showing the experimental results of the effect of mobocetinib succinate on the motility of Caenorhabditis elegans. Figure 9 A schematic diagram showing the experimental results of the effect of osimertinib on the locomotion ability of Caenorhabditis elegans; Figure 10 A schematic diagram showing the experimental results of the effect of mobocetinib succinate on the swallowing ability of Caenorhabditis elegans. Figure 11 This is a schematic diagram illustrating the experimental results of the effect of osimertinib on the motility and swallowing ability of Caenorhabditis elegans. Detailed Implementation

[0014] Aging involves the gradual decline of many functions in an organism, and its regulatory mechanisms are complex. Therefore, multiple intervention methods are needed to achieve the goal of delaying aging. In previous work screening anti-aging active molecules, the inventors discovered that the three EGFR inhibitor molecules mentioned in this invention have significant anti-aging activities, which are demonstrated by the extension of lifespan, improved motility and swallowing ability, and enhanced stress resistance in *C. elegans*.

[0015] The anti-aging effects of the three EGFR inhibitor molecules mentioned in this invention differ from their previously discovered effects of inhibiting tumor cell growth by suppressing the activity of EGFR mutant kinases. Therefore, this invention provides a novel research direction for studying the new mechanisms of action of these three EGFR inhibitor molecules, demonstrating creativity and significant beneficial effects.

[0016] The three EGFR inhibitor molecules of this invention are already marketed drugs, and their good therapeutic effects, drug metabolism parameters, and generally non-toxicity make them ideal drugs for anti-aging.

[0017] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. However, the scope of protection of the present invention is not limited to the content described, and it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments described. Rather, these embodiments are provided to provide a more thorough understanding of the present invention. Unless otherwise specified, the methods in the embodiments are conventional methods, and the reagents used are conventional commercially available reagents or reagents prepared according to conventional methods unless otherwise specified. The nematode strain used in the experiment was the common N2 nematode, which was donated by Professor Zou Chenggang of Yunnan University and originally came from the Caenorhabditis elegans Center of the University of Minnesota (CGC, https: / / cgc.umn.edu / ).

[0018] Example 1: A study on the effects of osimertinib, mobocetinib, and mobocetinib succinate on the lifespan of Caenorhabditis elegans.

[0019] After nematodes synchronized in NGM medium reached the L4 stage, they were transferred to 96-well plates for liquid culture (approximately 15 nematodes per well) to study the effects of different factors on nematode lifespan. Each well contained 200 μL of culture medium, including 100 μM FUdR (5-fluorouridine) to inhibit nematode reproduction; osimertinib, mobocetinib, and mobocetinib succinate were applied at a final concentration of 30 μM. A blank control group, a DMSO-treated control group (DMSO final concentration 3‰ v / v), and a positive control group (metformin final concentration 100 μM) were also included. Each treatment group was tested in triplicate, and statistical significance was required. Nematodes in each well were counted every other day to assess survival. Finally, survival curves were plotted using PRSIMGraphPad 8.0.2 software, and the mean lifespan and standard deviation (SD) of each group were calculated. The statistical analysis results of the lifespan experiments (as shown in Table 1) indicate that 30 μM mobocictinib, mobocictinib succinate, and osimertinib all prolonged the lifespan of nematodes, and the lifespan extension rates were all greater than those of 100 μM metformin. Furthermore, 3‰ v / v DMSO did not show significant toxicity in nematodes, indicating the reliability of the lifespan experiment results. The nematode survival curves from the relevant experiments are shown below. Figure 1 , Figure 2 and Figure 3 As shown.

[0020] Table 1: Statistical Table of Lifetime Experiment Results .

[0021] Example 2: The study on the effects of osimertinib and mobocictinib succinate on the stress resistance, motility and swallowing ability of Caenorhabditis elegans (mobocictinib and mobocictinib succinate are essentially the same drug, and previous studies have shown that mobocictinib succinate has relatively better anti-aging activity than mobocictinib, so mobocictinib succinate was chosen for this study).

[0022] After the synchronized nematodes cultured in NGM medium entered the L4 stage, they were treated with the drug. A blank control group and a DMSO-treated control group were also set up. The concentrations of DMSO and the drug were the same as those used in the lifespan experiment. One week after treatment, relevant phenotypic analyses were performed (nematodes were transferred to 96-well plates using M9 buffer), including heat stress analysis (nematodes were heat-treated at 37°C for 1 hour, then cultured at 20°C for 1 day, and the survival rate was calculated), oxidative stress analysis (nematodes were treated with 1.5‰ v / v H2O2 for 2 hours, and the survival rate was calculated), movement analysis (the number of complete back-and-forth swings of the nematode's body within 30 seconds was measured, with one swing to the left and right counted as one complete swing), and swallowing analysis (the number of complete pharyngeal pump cycles of the nematode within 30 seconds was measured, with one complete contraction and relaxation of the pharyngeal pump counted as one pharyngeal pump cycle). The bar chart was drawn using PRSIM GraphPad 8.0.2 software, and the significance was analyzed by paired samples t-test (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001).

[0023] Heat stress experiments revealed that both 30 μM mobocetinib succinate and osimertinib significantly improved the heat stress resistance of nematodes (as shown in Figure 1). Figure 4 and Figure 5 As shown in the figure, p < 0.001. Compared with the control group (59.14%), the survival rate of mobocictinib succinate increased to 84.97%, and the survival rate of osimertinib increased to 79.91%; among them, the survival rate of mobocictinib succinate was slightly higher than that of metformin at 100 μM (84.28%).

[0024] Oxidative stress experiments revealed that both 30 μM mobocetinib succinate and osimertinib significantly enhanced the antioxidant capacity of nematodes (as shown in Figure 1). Figure 6 and Figure 7 As shown, p < 0.001. Compared to the control group (61.96%), osimertinib improved the survival rate to 86.01%, which was stronger than metformin at 100 μM (80.46%); compared to the control group (59.27%), mobocetinib succinate improved the survival rate to 87.67%, both of which were stronger than metformin at 100 μM (80.61%).

[0025] Motion analysis revealed that both 30 μM mobocetinib succinate and osimertinib significantly improved the motility of nematodes (as shown in Figure 1). Figure 8 and Figure 9As shown, p < 0.0001, where body beding represents the number of swings. Compared to the control group (approximately 45.65 swings), osimertinib increased the number of swings to approximately 54.00, slightly lower than metformin at 100 μM (approximately 54.75 swings); compared to the control group (approximately 48.00 swings), mobocetinib succinate increased the number of swings to approximately 60.90, slightly lower than metformin at 100 μM (approximately 61.93 swings).

[0026] Analysis of swallowing behavior revealed that both 30 μM mobocetinib succinate and osimertinib significantly improved the swallowing ability of nematodes (as shown in Figure 1). Figure 10 and Figure 11 As shown, p < 0.0001, where pharyngeal pumping represents the number of swallows. Compared to the control group (approximately 51.55 swallows), osimertinib increased the number of swallows to approximately 65.65, higher than metformin at 100 μM (approximately 61.45 swallows); compared to the control group (approximately 56.77 swallows), mobocetinib succinate increased the number of swallows to approximately 63.90, slightly higher than metformin at 100 μM (approximately 62.67 swallows).

Claims

1. Application of EGFR inhibitor drugs in the preparation of anti-aging drugs.

2. The application according to claim 1, characterized in that, The EGFR inhibitor drugs are selected from osimertinib, mobocetinib, and mobocetinib succinate.

3. The application according to claim 1, characterized in that, The anti-aging drugs mentioned are those that delay aging or treat related diseases that accompany the aging process.

4. The application according to claim 1, characterized in that, The anti-aging drug contains a pharmaceutically acceptable carrier.

5. The application according to claim 1, characterized in that, The anti-aging drug is selected from one or more of the following dosage forms: tablets, pills, capsules, granules, microcapsule tablets, suspensions, drop pills, oral liquids, injections, aerosols, suppositories, and subcutaneous dosage forms.

6. The application according to claim 2, characterized in that, The EGFR inhibitor drugs mentioned include osimertinib, mobocetinib, and mobocetinib succinate, as well as novel combination drugs prepared by combining them with other active pharmaceutical ingredients.

7. The application according to claim 4, characterized in that, The carrier includes one or more of the following: calcium carbonate, calcium phosphate, calcium sulfate, sucrose, glucose, lactose, fructose, xylitol, sorbitol, starch, starch paste, cellulose derivatives, gelatin, polyvinylpyrrolidone, sodium chloride, dextrin, stearic acid, magnesium stearate, calcium stearate, vegetable oil, polyethylene glycol, sterile phosphate-buffered saline, saline, and Ringer's solution.

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