CN-121971446-A - Application of Nur77 regulation active ingredient and anti-tumor drug

Abstract

The application belongs to the technical field of active compounds, and particularly relates to application of Nur77 regulation active ingredients and an anti-tumor drug, wherein in the process of taking up nutrient substances through macropolympic fluid in a microenvironment with nutrition, nur77 regulation active ingredients provided by the application promote the specific combination of an LBD binding domain of Nur77 and ATP6V1A, excessively activate macropolympic fluid, inhibit the expression of a macropolympic fluid related signal path such as mTOR and the like, destroy the nutrition perception and metabolic steady state of tumor cells, induce giant bubble death of cells, and can show remarkable curative effect on metabolic reprogramming solid tumors such as castration resistant prostate cancer and the like under lower concentration, thereby solving the technical problem that the conventional active ingredients are difficult to specifically interfere with the macropolympic fluid.

Inventors

• Jiang Guanmin
• QIN JINGBO
• CHEN XIAOHUI
• HE HONGYING
• SHI MENGTING

Assignees

• 中山大学附属第五医院

Dates

Publication Date

20260505

Application Date

20260213

Claims (10)

1. 1. The application of the Nur77 regulation active ingredient in preparing the Nur77 regulator is characterized in that the chemical structural formula of the Nur77 regulation active ingredient is shown as a formula I; Formula I.
2. 2. The application of Nur77 regulation active ingredients in preparing a regulator for promoting the specific binding of Nur77 and ATP6V1A is characterized in that the chemical structural formula of the Nur77 regulation active ingredients is shown as formula I; Formula I.
3. 3. The application of Nur77 regulation active ingredients in preparing a regulator for promoting the LBD binding domain and ATP6V1A specific binding of Nur77 is characterized in that the chemical structural formula of the Nur77 regulation active ingredients is shown as formula I; Formula I.
4. 4. Use of Nur77 regulatory active ingredient in the preparation of a modulator that promotes the specific binding of the LBD binding domain of Nur77 to ATP6V1A and inhibits the metabolic pathway of mTOR.
5. 5. The application of a modulator in preparing an antitumor drug for metabolizing reprogramming solid tumors is characterized in that the modulator is selected from a Nur77 modulator according to claim 1, a Nur77 and ATP6V1A specific binding promoting modulator according to claim 2, a Nur77 LBD binding domain and ATP6V1A specific binding promoting modulator according to claim 3 or a Nur77 modulator active ingredient according to claim 4 in preparing a Nur77 LBD binding domain and ATP6V1A specific binding promoting and mTOR metabolic pathway inhibiting modulator.
6. 6. The use according to claim 4, wherein the metabolic reprogramming solid tumor is at least one of prostate cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer, colorectal cancer, ovarian cancer, melanoma, liver cancer, osteosarcoma, bladder cancer, glioma, head and neck squamous carcinoma, endometrial cancer, esophageal cancer.
7. 7. An antitumor drug for metabolizing a reprogrammed solid tumor, which is characterized by comprising the modulator of claim 4 and a pharmaceutical adjuvant.
8. 8. The anti-tumor drug for metabolizing reprogrammed solid tumor of claim 7, wherein the dosage form of the anti-tumor drug is at least one of powder injection, oral preparation, ointment, liniment and patch.
9. 9. The anti-tumor drug for metabolizing reprogrammed solid tumor of claim 7, wherein the pharmaceutical adjuvant is at least one of a lyoprotectant, an injection solvent, a solubilizer, a buffer, a suspending agent, a filler, a disintegrant, an adhesive, a lubricant, a cream base, and a transdermal enhancer.
10. 10. An antitumor drug for metabolizing a reprogrammed solid tumor according to claim 9, wherein said lyoprotectant is selected from mannitol; The injection solvent is at least one selected from water for injection, sodium chloride injection and glucose injection; The solubilizer is at least one selected from hydroxypropyl-beta-cyclodextrin, poloxamer 188 and polyoxyethylene castor oil; the buffer is at least one selected from citrate buffer, acetate buffer and phosphate buffer; the suspending agent is at least one selected from sodium carboxymethyl cellulose, hypromellose and povidone; the filler is at least one selected from microcrystalline cellulose and starch; the disintegrating agent is at least one selected from sodium carboxymethyl starch, crospovidone and croscarmellose sodium; the adhesive is at least one selected from hypromellose, povidone, starch slurry and sodium carboxymethyl cellulose; The lubricant is at least one of magnesium stearate and talcum powder; The cream base is selected from at least one of vaseline, lanolin and glycerol; the transdermal enhancer is selected from azone; The backing material of the patch is at least one selected from non-woven fabrics, plastic films and aluminum-plastic composite films.

Description

Application of Nur77 regulation active ingredient and anti-tumor drug Technical Field The application belongs to the technical field of active compounds, and particularly relates to application of Nur77 regulation active ingredients and an anti-tumor drug. Background Giant pinocytosis (Macropinocytosis) is a non-selective endocytosis process depending on actin reconstruction, tumor cells can be degraded into amino acid, lipid and saccharide by taking extracellular soluble protein, necrotic cell fragments, lipid and other substances, and solid tumors with metabolic reprogramming characteristics can actively change self metabolic modes to adapt to survival and proliferation, and energy is obtained through abnormal metabolic pathways such as amino acid, lipid and saccharide, so that the giant pinocytosis is favorable for the growth and survival of the solid tumors with metabolic reprogramming characteristics in a nutritional deficient microenvironment and drug resistance occurs. At present, partial literature, such as the group Su Hua of the double denier university, reports that the tumor cells are activated to take up extracellular nutrition through RAS-V-ATPase/SDC1, EGFR-RAC1-PAK1, DDR 1-NF-kappa B-p62/SQSTM1-NRF2 and other approaches in the literature review of 'molecular regulation mechanism research progress of tumor megapotion', the nuclear receptor Nur77 (also called NR4A 1) plays an important role in regulating and controlling cell metabolism, and can induce tumor cells to generate excessive activation and giant bubble death (Methuosis) of megapotion through regulating and controlling the activity of the nuclear receptor Nur77, so that the giant bubble death is a non-apoptotic cell death mode which is caused by the disturbance of the giant cell potion process and finally leads to the reduction of metabolic activity and the rupture of cell membranes, and the novel bioactive compound is developed to be used as a Nur77 regulator, and the tumor cells and the giant cell death can be induced to have the characteristics of high metabolic regulation and control strategy of the giant cell death. Prior studies have shown that prostate cancer cell proliferation is strongly dependent on the androgen-androgen receptor (Androgen Receptor, AR) signaling axis, and that androgen deprivation therapy (Androgen Deprivation Therapy, ADT) is still effective in inhibiting tumor growth in early prostate cancer patients, whereas most patients develop castration resistance within 18-24 months of androgen deprivation therapy, castration resistant prostate cancer (Castration-RESISTANT PROSTATE CANCER, CRPC) is one of the leading causes of death in prostate cancer patients in late stages of disease progression following androgen deprivation therapy, whereas until now, the specific biological function of Nur77 in castration resistant prostate cancer, particularly the mechanism of action in castration resistant prostate cancer cell-megacell-dependent nutrient acquisition, has not been systematically studied and elucidated, and the prior art has not provided an effective method capable of specifically interfering with Nur77 function to inhibit castration reprogramming and growth of castration resistant prostate cancer cells. Disclosure of Invention In view of the above, the application provides an application of Nur77 regulatory active ingredients and an anti-tumor drug, which are used for solving the technical problem that the existing active ingredients are difficult to specifically interfere with megacell. The first aspect of the application provides application of Nur77 regulation and control active ingredients in preparing Nur77 regulator, wherein the chemical structural formula of the Nur77 regulation and control active ingredients is shown as formula I; Formula I. The application provides an application of Nur77 regulation active ingredient in preparing a regulator for promoting Nur77 and ATP6V1A specific binding, wherein the chemical structural formula of the Nur77 regulation active ingredient is shown in formula I; Formula I. The third aspect of the application provides an application of Nur77 regulation active ingredient in preparing a regulator for promoting LBD binding domain and ATP6V1A specific binding of Nur77, wherein the chemical structural formula of the Nur77 regulation active ingredient is shown as formula I; Formula I. In a fourth aspect, the application provides the use of a Nur77 regulatory active ingredient in the preparation of a modulator that promotes the specific binding of the LBD binding domain of Nur77 to ATP6V1A and inhibits mTOR metabolic pathways. The application provides an application of a regulator in preparing an anti-tumor medicament for metabolizing reprogramming solid tumors, wherein the regulator is selected from a Nur77 regulator in the first aspect, a Nur77 and ATP6V1A specific binding promoting regulator in the second aspect, a Nur77 specific binding promoting regulator in the third aspe