CN-121971462-A - Application of harpagoside in preparation of medicine for inhibiting STUB1

Abstract

The invention discloses application of harpagoside in preparation of a medicament for inhibiting STUB1, wherein the harpagoside can be used as a specific inhibitor of E3 ubiquitin ligase STUB 1. Through inhibiting STUB1, the harpagoside can effectively block the GR ubiquitination process mediated by the harpagoside, so that the GR is prevented from being degraded by a proteasome, and the stabilization of the GR protein level is finally realized. The treatment effect of the hormone in the noise hearing loss animal model can be obviously improved by combining the harpagoside and the glucocorticoid, and the effect is better than that of the single-use hormone treatment.

Inventors

• TIAN CHUNJIE
• WEI YUXIN
• Mao Qiyang
• LIU XIAOYU
• WANG HAN
• WANG PENG
• LIU TING
• TIAN YE
• CHEN WEIBANG
• LIU YINGQI
• ZHENG ZIYING
• GAO WENYA

Assignees

• 广东医科大学附属医院

Dates

Publication Date

20260505

Application Date

20251121

Claims (9)

1. 1. Use of harpagoside, or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof, in the manufacture of a medicament for inhibiting STUB 1.
2. 2. Use of harpagoside or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof in the manufacture of a medicament for the treatment and/or amelioration of noise hearing loss.
3. 3. Use of harpagoside, or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof, in the manufacture of a medicament for the treatment and/or amelioration of a GR dysfunctional disorder.
4. 4. The use according to claim 3, wherein the GR dysfunction disease comprises an inflammatory, autoimmune and/or neurodegenerative disease.
5. 5. The use of harpagoside in combination with a glucocorticoid for the manufacture of a medicament for inhibiting STUB1, or for the manufacture of a medicament for treating noisy hearing loss, or for the manufacture of a medicament for treating GR dysfunction.
6. 6. The use according to claim 5, wherein the glucocorticoid comprises at least one of dexamethasone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone, fluticasone, budesonide, mometasone, ciclesonide.
7. 7. A pharmaceutical composition characterized in that the active ingredients thereof comprise harpagoside and at least one glucocorticoid.
8. 8. The pharmaceutical composition of claim 7, wherein the glucocorticoid comprises hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, fluticasone, budesonide, mometasone, ciclesonide.
9. 9. Use of the pharmaceutical composition of claim 7 for the treatment or amelioration of noise-induced hearing loss.

Description

Application of harpagoside in preparation of medicine for inhibiting STUB1 Technical Field The invention relates to the technical field of medicines, in particular to application of harpagoside in preparation of a medicine for inhibiting STUB 1. Background Glucocorticoids (Glucocorticoid, GC) are core drugs used clinically to inhibit inflammatory responses. Its pharmacological action depends on binding to intracellular glucocorticoid receptors. However, there is a general contradiction in clinical practice that high levels of hormone, whether originating from stress or high dose medication, can instead reactively cause degradation of its own receptor, the glucocorticoid receptor (Glucocorticoid receptor, GR). This negative feedback mechanism results in decreased sensitivity of the target cells to the hormone, forms "hormone resistance", severely limits the anti-inflammatory efficacy of the hormone, and forces the use of larger doses of hormone clinically, thereby increasing the risk of systemic side effects. Studies have shown that GR degradation occurs primarily through the ubiquitin-proteasome pathway, with E3 ubiquitin ligase STUB1 being a key executive molecule responsible for "attaching" a ubiquitination tag to the GR protein, leading to its clearance by the proteasome. Thus, in theory, inhibition of this degradation process is an effective strategy to stabilize GR, enhancing hormonal effects. Currently, while there are a number of broad spectrum proteasome inhibitors (e.g., MG-132) that block degradation of a variety of proteins including GR, such inhibitors lack specificity and have been demonstrated to be significantly cytotoxic and have no potential for clinical use. Therefore, there is an urgent need to find a small molecule drug capable of specifically targeting the GR degradation upstream pathway, safely and effectively stabilizing the GR protein, so as to solve the bottleneck problem existing in the current hormone therapy. Disclosure of Invention Therefore, the main purpose of the invention is to provide a small molecular compound capable of specifically blocking the GR ubiquitination degradation path, stabilizing GR protein and further synergistically enhancing the anti-inflammatory action of hormone. Through inhibiting STUB1, the harpagoside can effectively block the GR ubiquitination process mediated by the harpagoside, so that the GR is prevented from being degraded by a proteasome, and the stabilization of the GR protein level is finally realized. When the GR protein level is stabilized, the sensitivity of the cell to the glucocorticoid is restored and enhanced, so that the hormone can exert its anti-inflammatory effect more effectively. The invention further proves that the treatment effect of the hormone in the noise hearing loss animal model can be obviously improved by combining the harpagoside and the glucocorticoid (such as dexamethasone), and the effect is better than that of the treatment by singly using the hormone. In order to achieve the above purpose, the technical scheme of the invention is as follows: in a first aspect, the invention provides the use of a halbacoside, or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof, in the manufacture of a medicament for inhibiting a STUB 1. In a second aspect of the invention there is provided the use of harpagoside, or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof, in the manufacture of a medicament for the treatment and/or amelioration of noise hearing loss. In a third aspect of the invention there is provided the use of harpagoside, or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof, in the manufacture of a medicament for the treatment and/or amelioration of a GR dysfunctional disease. Further, the GR dysfunction disease includes inflammation, autoimmune disease, and/or neurodegenerative disease. Among them, harpagoside has noise hearing impairment as main indication. The chemical structural formula of the small molecular compound Harpagoside (HARPAGIDE) used in the invention is shown as follows: 。 harpagoside is a natural product, and is a main active ingredient isolated from a plant of the Scrophulariaceae family such as Harpagophytum procumbens (Harpagophytum procumbens, commonly known as "devil's claw"). The structure has the following characteristics: 1. bicyclic framework the molecule comprises a bicyclic framework consisting of two fused rings. One of the rings is a six-membered ring and the other is a five-membered ring. 2. Four-ring system the molecule is a complex four-ring system consisting of three six-membered rings and one five-membered ring in the sense of unity, wherein the two rings (one six-membered ring and one five-membered ring) are fused together by carbon-carbon bonds to form the core skeleton. 3. Chiral center-the molecule contains a plurality of chiral centers, which can be judged by its stereochemical configuration (bonds shown as so