WO2024221689A1 - Use of jak-hadc dual-target inhibitor and drug for treating inflammatory skin diseases - Google Patents

Abstract

The use of a JAK-HADC dual-target inhibitor and a drug for treating inflammatory skin diseases, which belong to the technical field of medicine. The use of a JAK-HADC dual-target inhibitor in the preparation of a drug for treating inflammatory skin diseases. The present invention relates to a compound or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug, and a solvate thereof, in particular to the use of the compound as a JAK-HDAC dual-target inhibitor and an optional pharmaceutically acceptable carrier thereof in the treatment of JAK and HDAC-related inflammatory skin diseases, especially in the treatment of atopic dermatitis, psoriasis, vitiligo and alopecia areata.

Description

Application of a JAK-HADC dual-target inhibitor and drug for treating inflammatory skin diseases Technical Field

The present invention relates to the field of medical technology, and in particular to an application of a JAK-HADC dual-target inhibitor and a drug for treating inflammatory skin diseases.

Background Art

JAK kinase (Janus Kinase, JAK) is a family of intracellular non-receptor tyrosine kinases and is also an important signal sensor for many cytokines, interferons, etc. The downstream substrate of JAK is a type of signal transducer and activator of transcription (STAT). STAT family proteins can bind to the DNA of the target gene regulatory region, thereby regulating the transcription process of specific genes. In terms of action, JAK is a pathway necessary for immune response, and when inflammation occurs, overactivation of JAK will in turn promote disease progression. The JAK-STAT signaling pathway mediates the signal transduction of most cytokines in cells, such as interleukins (IL) and interferons (IFN), and different receptors can activate different subtypes of JAK kinases, thereby showing differentiated biological functions. The JAK-STAT signaling pathway has a wide range of functions and is related to the pathogenesis of inflammatory diseases and autoimmune diseases. It participates in many important biological processes such as proliferation, differentiation, apoptosis and immune regulation of immune cells. Therefore, targeted blocking of the JAK-STAT pathway can inhibit the pathophysiological process of autoimmune diseases or allogeneic transplant rejection, thereby improving the clinical symptoms of such patients and improving the quality of life of patients.

As a family of epigenetic enzymes, histone deacetylases (HDACs) remove acetyl groups from lysine on histones and other proteins, which plays an important role in various cellular functions including gene regulation, transcription, cell proliferation, differentiation and death. HDACs were originally discovered to deacetylate histones, affecting the tightness of DNA binding to histones, thereby regulating gene expression. Histone acetyltransferases (HATs) add acetyl groups to histone tails, causing chromatin relaxation, and HDACs remove acetyl groups, causing chromatin tightening. HDACs are enzymes that play a key role in epigenetic regulation of gene expression by remodeling chromatin. Inhibition of HDACs is a prospective therapeutic approach to reverse epigenetic changes in inflammatory diseases. The expression of cytokines (IL-1, IL-6, IL-8 and IL-12, TNF-α, IFN-γ, etc.), chemokines, and growth factors of the inflammatory cascade is regulated by epigenetic mechanisms. The result of HDAC inhibition is an open chromatin state, which will return activated inflammatory cells to a normal state. HDAC inhibition has the potential to normalize abnormal pathological pathways and is expected to become a treatment option for autoimmune diseases.

JAK inhibitors have a wide range of applications ranging from autoimmune diseases to cancer to Alzheimer's disease. Known JAK inhibitors include Tofacitinib, Delgocitinib, PF-06651600, Baricitinib, Abrocitinib, Upadacitinib, Ruxolitinib, and Filgotinib, etc. HDAC inhibitors such as Vorinoda and Romidin can inhibit one or more deacetylases.

In the prior art, JAK and HDAC inhibitors are used to treat tumors.

Summary of the invention

In view of this, the purpose of the present invention is to provide an application of a JAK-HADC dual-target inhibitor and a drug for treating inflammatory skin diseases. The present invention uses a JAK-HADC dual-target inhibitor to treat inflammatory skin diseases, providing a new use of the inhibitor.

In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

The present invention provides an application of a JAK-HADC dual-target inhibitor in the preparation of a drug for treating inflammatory skin diseases, wherein the JAK-HADC dual-target inhibitor has a structure shown in Formulas 1 to 5 or a pharmaceutically acceptable salt thereof:

Preferably, the inflammatory skin diseases include atopic dermatitis, psoriasis, vitiligo and alopecia areata.

Preferably, the JAK-HADC dual-target inhibitor is an enantiomer or a racemate.

Preferably, the JAK-HADC dual-target inhibitor is used in the form of a solution, and the effective concentration of the JAK-HADC dual-target inhibitor in the solution is 0.01 to 1000 μM.

The present invention also provides a drug for treating inflammatory skin diseases, comprising the JAK-HADC dual-target inhibitor described in the above technical solution.

Preferably, a pharmaceutically acceptable carrier is also included.

Preferably, the dosage form of the drug for treating inflammatory skin diseases includes tablets, injections, capsules, granules, pills, powders, oral liquids, sustained-release preparations, controlled-release preparations, creams, ointments, liniments, lotions or pharmaceutically acceptable dosage forms of nanoformulations.

Preferably, the effective concentration of the JAK-HADC dual-target inhibitor in the drug for treating inflammatory skin diseases is 0.01 to 1000 μM.

The present invention proposes for the first time the use of a JAK-HADC dual-target inhibitor in the preparation of drugs for the treatment of inflammatory skin diseases, which expands the application of the compound. There is a synergistic effect between the JAK and HDAC targets. JAK is an enzyme involved in many important biological processes such as proliferation, differentiation, apoptosis and immune regulation of immune cells. Inhibition of JAK can block the signal transduction of most cytokines mediated by JAK kinase in immune cells; HDAC is an enzyme that plays a key role in the epigenetic regulation of cytokines in the inflammatory cascade. Inhibition of HDAC can regulate the expression of cytokines (IL-1, IL-6, IL-8 and IL-12, TNF-α, IFN-γ, etc.), chemokines, and growth factors that reduce the inflammatory cascade through epigenetic mechanisms, which will return activated inflammatory cells to a normal state. Blocking the dual targets of JAK and HDAC at the same time has a much higher inhibitory effect on abnormal inflammation than blocking them separately, which can achieve the inhibition of upstream and downstream factors of the inflammatory pathway, and a small dose of JAK-HDAC dual-target inhibitor can achieve the effect of completely inhibiting the inflammatory response, thereby reducing the adverse reactions of large doses of drugs to subjects. For example, as shown in the examples, a low dose (0.8 μM) of A16 can completely inhibit the inflammatory response of macrophages.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the tolerance curve of RAW 264.7 cells to A9 compound;

Figure 2 is the tolerance curve of RAW 264.7 cells to A16 compound;

FIG3 is a tolerance curve of HaCaT cells to A9 compound;

FIG4 is a tolerance curve of HaCaT cells to A16 compound;

FIG5 shows the inhibitory effect of JAK-HADC dual-target inhibitor on NO production in macrophages under inflammatory conditions;

FIG6 shows the inhibitory effects of A9 and A16 on TNF-α in RAW264.7 cells;

FIG7 shows the inhibitory effects of A9 and A16 on IL-6 in RAW264.7 cells;

Figure 8 shows the skin lesions of psoriasis mice in each group;

Figure 9 shows the PASI scores of psoriasis mice in each group;

FIG10 shows the weight change rate of psoriasis mice in each group;

Figure 11 is a HE-stained pathological section to evaluate the psoriasis condition of mice in each group;

Figure 12 shows the IL-6 cytokine levels in each group of psoriasis mice;

FIG13 shows the TSLP cytokine levels in each group of psoriasis mice;

FIG14 shows the number of Th17 cells in CD4 cells of mice in each group;

FIG15 shows ear inflammation in each group of atopic dermatitis mice;

Figure 16 shows the SCORAD scores of mice with atopic dermatitis in each group;

Figure 17 shows the changes in ear thickness of mice with atopic dermatitis in each group;

FIG18 is a HE-stained pathological section to evaluate the atopic dermatitis condition of mice in each group;

Figure 19 is a toluidine blue stained pathological section to evaluate the atopic dermatitis condition of mice in each group;

Figure 20 shows the number of Th1 and Th2 cells in CD4 cells of mice in the Control group;

Figure 21 shows the number of Th1 and Th2 cells in CD4 cells of mice in the Model group;

Figure 22 shows the number of Th1 and Th2 cells in CD4 cells of mice in the Treat A9 group;

Figure 23 shows the number of Th1 and Th2 cells in CD4 cells of mice in the Treat A16 group.

DETAILED DESCRIPTION

The present invention provides an application of a JAK-HADC dual-target inhibitor in the preparation of a drug for treating inflammatory skin diseases, wherein the JAK-HADC dual-target inhibitor has a structure shown in Formulas 1 to 5 or a pharmaceutically acceptable salt thereof:

The present invention has no particular limitation on the source of the JAK-HADC dual-target inhibitor, and it can be prepared by a preparation method well known to those skilled in the art, for example, it can be synthesized by the Naval Medical University of the Chinese People's Liberation Army (Second Military Medical University).

In the present invention, the inflammatory skin diseases preferably include atopic dermatitis, psoriasis, vitiligo and alopecia areata.

In the present invention, the JAK-HADC dual-target inhibitor is preferably an enantiomer or a racemate.

In the present invention, the JAK-HADC dual-target inhibitor is preferably used in the form of a solution, and the effective concentration of the JAK-HADC dual-target inhibitor in the solution is preferably 0.01 to 1000 μM.

The present invention also provides a drug for treating inflammatory skin diseases, comprising the JAK-HADC dual-target inhibitor described in the above technical solution or a pharmaceutically acceptable salt thereof.

In the present invention, it is preferred to further include a pharmaceutically acceptable carrier.

In the present invention, the carrier refers to the ingredients other than the active molecule in the drug administration preparation, which is non-toxic to the subject or has extremely low toxicity within the dosage range, and preferably includes pharmaceutical excipients, such as excipients, buffers, absorption promoters, emulsifiers, thickeners, surfactants, antioxidants, preservatives and flavors. The creams, ointments, liniments and lotions are external preparations.

In the present invention, the dosage form of the drug for treating inflammatory skin diseases preferably includes tablets, injections, capsules, granules, pills, powders, oral liquids, sustained-release preparations, controlled-release preparations, creams, ointments, liniments, lotions or pharmaceutically acceptable dosage forms of nanoformulations.

In the present invention, the effective concentration of the JAK-HADC dual-target inhibitor in the drug for treating inflammatory skin diseases is preferably 0.01 to 1000 μM.

In the present invention, the drug for treating inflammatory skin diseases is preferably placed in a container.

Terminology of the present invention

The term Janus kinase refers to a non-receptor tyrosine kinase that transduces cytokine-mediated signals through the JAK-STAT pathway. Janus kinases can be abbreviated as "JAK". The known JAK family mainly includes four members, namely: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Jansu kinase 3 (JAK3) and tyrosine kinase 2 (TYK2). Human Janus kinase 1 is encoded by the gene JAK1, human Janus kinase 2 is encoded by the gene JAK2, human Janus kinase 3 is encoded by the gene JAK3, and human tyrosine kinase 2 is encoded by the gene TYK2.

The term HDAC refers to histone deacetylase, which can be divided into four categories according to their function and DNA sequence similarity, namely histone deacetylase type I, II, III, and IV (HDAC 1-4).

The term container may be of the type and shape commonly used in pharmaceutical preparations, such as a tube, bottle, can, etc., and its material may be organic polymer or glass or other acceptable materials.

In order to further illustrate the present invention, the application of the JAK-HADC dual-target inhibitor provided by the present invention and the drug for treating inflammatory skin diseases are described in detail below in combination with examples, but they should not be construed as limiting the scope of protection of the present invention.

In a specific embodiment of the present invention, the A2-A16 compound used is synthesized by the School of Pharmacy of the Naval Medical University of the Chinese People's Liberation Army (Second Military Medical University). In an embodiment of the method for treating inflammatory skin diseases according to the present invention, the content of the A2-A16 compound in the external preparation is 0.01-10wt%, the concentration in the skin tissue is 0.1-100μM, and the plasma concentration is 0.01-20μM.

Example 1 Tolerance of RAW 264.7 cells (mouse macrophages) and HaCaT cells (human keratinocytes) to compounds A9 and A16

Experimental method: Take RAW264.7 cells or HaCaT cells in the logarithmic growth phase and pipette to form a single-cell dispersed suspension. After counting the cells, seed them into a 96-well plate at a density of 6.0×10 ³ cells/well and place them in a cell culture incubator for 24 hours to allow them to adhere to the wall. The cells were then replaced with a culture medium containing different concentrations of A9 and A16 compounds, and a control group without drugs was set up. After returning to the cell culture incubator for 24 hours, the upper culture medium of the 96-well plate was discarded. 100 μL of DMEM culture medium containing 10wt% CCK8 test solution was added to each well of cells, placed in a cell culture incubator and incubated for 60 minutes, and the OD value of each well at 450nm was measured using an enzyme reader, and the cell viability was calculated according to the following formula:

Cell viability (%) = (OD value of drug administration group - OD value of blank well) / (OD value of control group - OD value of blank well) × 100%. The OD value of the blank well is the OD value of the cell-free well at 450 nm in 100 μL of DMEM medium containing 10 wt% CCK8 test solution.

Experimental results: As shown in Figures 1 to 4, Figure 1 is the tolerance curve of RAW 264.7 cells to A9 compound, Figure 2 is the tolerance curve of RAW 264.7 cells to A16 compound, Figure 3 is the tolerance curve of HaCaT cells to A9 compound, and Figure 4 is the tolerance curve of HaCaT cells to A16 compound. It can be seen that A9 and A16 compounds showed no cytotoxicity to RAW264.7 cells and HaCaT cells below 100 μM, indicating that A9 and A16 compounds have good potential safety.

Example 2 Inhibitory effect of JAK-HADC dual-target inhibitor on NO production in macrophages under inflammatory conditions

Experimental method: Take RAW264.7 cells (mouse macrophages) in the logarithmic growth phase and pipette to form a single cell dispersion suspension. After counting the cells, they were seeded into a 24-well plate at a density of 1.0×10 ⁵ cells/well and placed in an incubator for 24 hours to allow them to adhere to the wall. Subsequently, the cells were replaced with culture medium containing different concentrations of JAK-HADC dual-target inhibitors, and a control group and a blank group were set up at the same time. After culturing for 1 hour, 10 μL of culture medium containing 50 μg/mL LPS and 200 ng/mL IFN-γ was added to each well except for the blank group, and 10 μL of ordinary culture medium was added to the blank group. After continuing to culture for 24 hours, the supernatant was collected. The specific steps of NO detection in the cell supernatant were operated according to the instructions of the NO detection kit (Shanghai Biyuntian Biotechnology Co., Ltd.), and the NO content and inhibition rate were calculated.

Formula: NO content [c/(μmol·L ^-1 )] = (average OD value of the assay tube - average OD value of the blank tube)/(average OD value of the standard tube - average OD value of the blank tube) × concentration of the standard × dilution multiple of the sample.

NO inhibition rate (%) = (average NO content in the control group - average NO content in the drug-treated group) / (average NO content in the control group - average NO content in the blank group) × 100%.

Experimental results: As shown in Figure 5. NO is a manifestation of macrophage inflammation. 50nM of JAK-HADC dual-target inhibitor can inhibit the NO production of Raw264.7 cells under inflammatory conditions. 800nM of JAK-HADC dual-target inhibitor makes the NO of Raw264.7 cells return to the baseline level, indicating that JAK-HADC dual-target inhibitor has a good anti-inflammatory effect.

Example 3 Inhibitory effects of A9 and A16 on the production of inflammatory factors in macrophages under inflammatory conditions

Experimental method: Take RAW 264.7 cells, plant them in a 24-well plate at a density of 1.0×10 ⁵ cells/well, and put them in an incubator for 24 hours to allow them to adhere to the wall. Then the cells were replaced with culture medium containing different concentrations of A9 and A16 compounds, and a control group and a blank group were set up. After 1 hour of culture, 10 μL of culture medium containing 50 μg/mL LPS and 200 ng/mL IFN-γ was added to each well except the blank group, and 10 μL of ordinary culture medium was added to the blank group. After continuing to culture for 24 hours, the supernatant was collected, and the content of TNF-α and IL-6 in the supernatant was determined according to the instructions of the ELISA kit.

TNF-α inhibition rate (%) = (average TNF-α content in the model control group - average TNF-α content in the drug administration group) / average TNF-α content in the model control group × 100%.

IL-6 inhibition rate (%) = (average IL-6 content in the model control group - average IL-6 content in the drug administration group) / average IL-6 content in the model control group × 100%.

Experimental results: As shown in Figures 6 and 7, Figure 6 shows the inhibitory effect of A9 and A16 on TNF-α of RAW264.7 cells, and Figure 7 shows the inhibitory effect of A9 and A16 on IL-6 of RAW264.7 cells. Since TNF-α and IL-6 play an important role in the onset of autoimmune diseases, especially inflammatory skin diseases, reducing the production of TNF-α and IL-6 is expected to treat such diseases. It can be seen that 50nM of A9 and A16 can inhibit the production of TNF-α and IL-6, two inflammatory factors of RAW264.7 cells, and 400nM of A9 and A16 can return the TNF-α and IL-6 of RAW264.7 cells to the baseline level, indicating that A9 and A16 compounds have good therapeutic effects on inflammatory skin diseases.

Example 4 Therapeutic effects of A2-A16 on psoriasis model mice

Experimental method: The mouse skin psoriasis model was established by imiquimod induction method. The specific method is as follows: 2 cm × 2 cm of the back skin of 8-week-old Balb/c mice was shaved. Starting from the second day after shaving, each mouse was applied with 70 mg of imiquimod ointment (imiquimod content 5%, produced by Sichuan Mingxin Pharmaceutical Co., Ltd.) at 8-9 am for model stimulation. At 19-20 pm, A9 content 0.2 wt% and A16 content 0. Modeling and drug administration were performed simultaneously for 6 days with 0.2wt% of the two creams. Photos were taken every day, and the PASI (Psoriasis area and severity index) scores were performed on the lesions in the drug-applied areas on the back of the mice to evaluate the success of the psoriasis modeling and the severity of psoriasis.

The PASI score includes the lesion area score and the lesion severity score.

The lesion area score is based on the percentage of surface area: 0 = no rash, 1 = 1% to 9%, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, and 6 = 90% to 100%.

The severity of skin lesions was evaluated based on erythema, infiltration, and scaling, with each feature scored from 0 to 4: 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

The lesion area score and lesion severity score were added together to obtain a total score ranging from 0 to 18 points.

After the last administration, the condition of the damaged skin tissue was observed, the damaged skin tissue was obtained and homogenate was prepared, and the psoriasis-related indicators of the damaged skin tissue of each group of mice were detected, and the diseased skin tissue was observed by tissue section staining; the spleen tissue of each group of mice was obtained and tissue homogenate was prepared, and the number of Th17 cells in CD4 cells was recorded using flow cytometry sorting technology.

Experimental results:

1. As shown in Figures 8 to 10, Figure 8 shows the skin damage of psoriasis mice in each group, Figure 9 shows the PASI scores of psoriasis mice in each group, and Figure 10 shows the weight change rate of psoriasis mice in each group. It can be seen that the PASI scores of psoriasis mice in the A9 and A16 treatment groups increased but the degree was slower than that of the model group, and the weight loss level was slower than that of the model group. The back scales of psoriasis mice in the A9 and A16 treatment groups were better than those in the model group, indicating that A9 and A16 have therapeutic effects on psoriasis.

2. As shown in Figure 11, HE-stained pathological sections were used to evaluate the psoriasis condition of mice in each group. Compared with the model group, the A9 and A16 treatment groups had less thickening of the spinous layer and less infiltration of inflammatory cells and eosinophils in the dermis.

3. As shown in Figures 12 and 13, Figure 12 shows the IL-6 cytokine levels in each group of psoriasis mice, and Figure 13 shows the TSLP cytokine levels in each group of psoriasis mice. It can be seen that the levels of psoriasis-related cytokines in mice treated with A9 and A16 were downregulated.

4. As shown in Figure 14 (the number of Th17 cells in CD4 cells of mice in each group), the proportion of Th17 cells in CD4 cells of mice in the A9 and A16 treatment groups was lower than that in the model group, indicating that A9 and A16 significantly inhibited the immune response of psoriasis mice and had a superior psoriasis treatment effect.

Example 4 The therapeutic effects of A9 and A16 on atopic dermatitis model mice

Experimental methods: The mouse skin atopic dermatitis model was established by calcipotriol induction method. The specific method is as follows: 9-week-old Balb/c mice were smeared with calcipotriol ethanol solution (calcipotriol content 1.7wt%, produced by MACKLIN) on the ears. From day 0 to day 7 of modeling, 100μL of calcipotriol ethanol solution was applied to the ears of each mouse at 9 am, and two creams with A9 content of 0.2wt% and A16 content of 0.2wt% were applied at 17 pm. Modeling and drug administration were carried out simultaneously for 10 days. Pictures were taken every day, and the atopic dermatitis SCORAD score was used to evaluate the severity of the lesions in the medicated area of the mouse ears. Ear lesions include three aspects: lesion area, lesion severity (including erythema, edema, exudation or crusting, epidermal exfoliation, skin thickening and dry skin), and itching.

Each symptom was rated from 0 to 3 points depending on the severity of the skin lesions, with no symptoms being 0 points, mild being 1 point, moderate being 2 points, and severe being 3 points.

SCORAD score = lesion area score/5 + 7 × severity score/2 + subjective symptom score. SCORAD mild: 0-24 points, moderate: 25-50 points, severe: >50 points, the highest score is 103 points.

After the last administration, the condition of the damaged skin tissue was observed, the damaged skin tissue was taken and homogenate was prepared, and the atopic dermatitis-related indicators of the damaged skin tissue of each group of mice were detected, and the diseased skin group was observed by tissue section staining; the spleen tissue of each group of mice was taken, homogenate was prepared for cell sorting, and the proportion of Th1 and Th2 cells in CD4 of the spleen tissue of each group of mice was detected.

Experimental results:

1. As shown in Figures 15 to 17, Figure 15 shows the ear inflammation of each group of atopic dermatitis mice, Figure 16 shows the SCORAD scores of each group of atopic dermatitis mice, and Figure 17 shows the changes in ear thickness of each group of atopic dermatitis mice. The ear inflammation of atopic dermatitis mice in the A9 and A16 treatment groups was better than that in the model group. The SCORAD scores of atopic dermatitis mice in the A9 and A16 treatment groups increased but to a lesser extent than the model group, and the weight loss level was slower than that in the model group, indicating that A9 and A16 have therapeutic effects on atopic dermatitis.

2. As shown in Figures 18 and 19, Figure 18 is a pathological section of HE staining to evaluate the atopic dermatitis of each group of mice, and Figure 19 is a pathological section of toluidine blue staining to evaluate the atopic dermatitis of each group of mice. It can be seen that the pathological sections of HE staining and toluidine blue staining evaluate the atopic dermatitis of each group of mice. Compared with the model group, the A9 and A16 treatment groups had less thickening of the spinous cortex, less infiltration of inflammatory cells and eosinophils in the dermis.

3. As shown in Figures 20 to 23, Figure 20 shows the number of Th1 and Th2 cells in CD4 cells of mice in the Control group, and Figure 21 shows the number of Th1 and Th2 cells in CD4 cells of mice in the Model group. Figure 22 is the number of Th1 and Th2 cells in CD4 cells of mice in Treat A9 group, and Figure 23 is the number of Th1 and Th2 cells in CD4 cells of mice in Treat A16 group. It can be seen that the proportion of Th1 and Th2 cells in CD4 cells of mice in A9 and A16 treatment groups was lower than that in the model group, indicating that A9 and A16 significantly inhibited the immune response of mice with atopic dermatitis and had superior therapeutic effects on atopic dermatitis.

The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims (8)

A use of a JAK-HADC dual-target inhibitor in the preparation of a drug for treating inflammatory skin diseases, wherein the JAK-HADC dual-target inhibitor has a structure shown in any one of Formulas 1 to 5 or a pharmaceutically acceptable salt thereof:
The use according to claim 1 is characterized in that the inflammatory skin diseases include atopic dermatitis, psoriasis, vitiligo and alopecia areata. The use according to claim 1 or 2, characterized in that the JAK-HADC dual-target inhibitor is an enantiomer or a racemate. The use according to claim 1 is characterized in that the JAK-HADC dual-target inhibitor is used in the form of a solution, and the effective concentration of the JAK-HADC dual-target inhibitor in the solution is 0.01 to 1000 μM. A drug for treating inflammatory skin diseases, characterized by comprising the JAK-HADC dual-target inhibitor according to claim 1. The drug for treating inflammatory skin diseases according to claim 5, further comprising a pharmaceutically acceptable carrier. The drug for treating inflammatory skin diseases according to claim 5, characterized in that the dosage form of the drug for treating inflammatory skin diseases includes tablets, injections, capsules, granules, pills, powders, The invention can be in the form of a pharmaceutically acceptable dosage form of a medicament, oral solution, sustained-release preparation, controlled-release preparation, cream, ointment, liniment, lotion or nanoformulation. The drug for treating inflammatory skin diseases according to claim 5, characterized in that the effective concentration of the JAK-HADC dual-target inhibitor in the drug for treating inflammatory skin diseases is 0.01 to 1000 μM.