[go: up one dir, main page]

WO2025112027A1 - Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique - Google Patents

Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique Download PDF

Info

Publication number
WO2025112027A1
WO2025112027A1 PCT/CN2023/135791 CN2023135791W WO2025112027A1 WO 2025112027 A1 WO2025112027 A1 WO 2025112027A1 CN 2023135791 W CN2023135791 W CN 2023135791W WO 2025112027 A1 WO2025112027 A1 WO 2025112027A1
Authority
WO
WIPO (PCT)
Prior art keywords
liver
cbp
acute
chronic
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2023/135791
Other languages
English (en)
Chinese (zh)
Inventor
罗成
王玉刚
张元元
施敏
陈潘宇
范仕杰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Tong Ren Hospital
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Tong Ren Hospital
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Tong Ren Hospital, Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Tong Ren Hospital
Priority to PCT/CN2023/135791 priority Critical patent/WO2025112027A1/fr
Publication of WO2025112027A1 publication Critical patent/WO2025112027A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention belongs to the field of biomedicine technology and relates to the application of targeted inhibition of p300/CBP in liver injury diseases, and specifically, to the application of targeted inhibition of p300/CBP in liver injury diseases, including acute and chronic liver injury and/or liver failure and chronic-acute liver failure.
  • the liver is an important organ for human metabolism and detoxification, and its functions are very important. However, in some cases, such as alcoholism, drug poisoning, viral infection, autoimmune liver disease, etc., the liver may suffer varying degrees of damage, leading to liver dysfunction and even acute liver failure, chronic liver damage, and chronic-acute liver failure.
  • Acute liver failure as a severe form of acute liver injury, occurs in a relatively short period of time (usually 1-26 weeks), manifested by rapid deterioration of liver function within days to weeks.
  • jaundice is a symptom of yellowing of the skin and mucous membranes
  • coagulation disorders such as bleeding tendency
  • high bilirubin high bilirubin
  • the condition of patients with acute liver failure often worsens in a short period of time, sometimes even leading to coma and multiple organ dysfunction within a few days.
  • Chronic liver injury refers to long-term damage or inflammation of the liver to varying degrees, which usually develops slowly over months or years and may be accompanied by gradual impairment of liver function. Chronic liver injury usually does not show acute symptoms, but gradually leads to fibrosis (liver fibrosis) and scarring (cirrhosis) of liver tissue. If not treated or controlled in time, chronic liver injury may eventually lead to serious complications such as liver dysfunction, portal hypertension, and hepatocellular carcinoma.
  • Acute-on-chronic liver failure is a serious liver disease that refers to the sudden onset of severe liver failure on the basis of chronic liver disease. It is mainly manifested by severe symptoms such as jaundice, coagulation disorders, and hepatic encephalopathy. It often develops into multiple organ failure and death. When the disease occurs, patients often need emergency treatment.
  • liver protection drugs such as alanine, glutathione, etc.
  • immunomodulatory drugs such as alanine, glutathione, etc.
  • antiviral drugs if viral infection is the main cause of liver function deterioration
  • supportive treatment drugs vitamins, mineral supplements
  • Inflammatory immune dysregulation plays a key role in acute liver failure, chronic liver injury and acute-on-chronic liver failure. This commonality involves multiple complex biological processes, including abnormal activation of immune cells, excessive release of inflammatory mediators, local inflammatory response caused by immune cell infiltration, and oxidative stress.
  • inflammatory immune dysregulation can usually be manifested as: systemic large-scale inflammatory response due to severe damage to liver cells; immune cells release a large number of inflammatory mediators, such as TNF- ⁇ and IL-6, which lead to aggravated inflammatory damage; acute liver failure may cause the failure of the immune system tolerance mechanism, causing the immune system to attack its own tissues and aggravate liver damage.
  • Immune dysregulation in chronic liver injury is usually manifested as: persistent low-grade inflammation, causing progressive liver fibrosis and cirrhosis; some immune cells are continuously activated in long-term liver inflammation, releasing inflammatory mediators, leading to liver tissue damage; the immune system may produce abnormal immune responses to liver tissue, leading to the development of autoimmune liver disease.
  • the situation is more complicated in the case of acute-on-chronic liver failure, which combines the characteristics of acute and chronic liver damage.
  • Immune dysregulation usually manifests as the characteristics of acute liver failure, but the patient already has a background of chronic liver damage, so it is often accompanied by obvious systemic inflammatory response (immune cell activation and release of large amounts of inflammatory mediators); at the same time, immunosuppression occurs and may cause the body to be unable to effectively respond to infection, increasing the risk of infectious complications; infection is one of the most common causes of ACLF deterioration.
  • CBP and p300 belong to the same protein family and are highly similar in structural motifs. They catalyze the acetylation of H3K18 and H3K27, respectively, and their genes are expressed in all mammalian cells.
  • the field of epigenetics to which the p300/CBP protein belongs is currently a hot topic of research. There is a direct link between the p300/CBP protein and the processes of immune cell proliferation, differentiation, and function. Moreover, targeted inhibition of p300/CBP has also been reported in recent years to regulate immune responses and inhibit the occurrence and development of various types of inflammation, such as rheumatoid arthritis.
  • p300/CBP inhibitors are a class of epigenetic drugs that can inhibit CBP
  • the activities of CREB-binding protein and p300 protein play an important role in the transcription and expression regulation of inflammatory immune genes. Therefore, targeted inhibition of p300/CBP has shown excellent performance in the treatment of a variety of inflammatory immune-related diseases.
  • the present invention aims to solve at least one of the technical problems in the related art to a certain extent.
  • one object of the present invention is to propose a new target and related method for preventing and/or treating acute and chronic liver damage diseases and acute-on-chronic liver failure.
  • p300/CBP inhibitors can significantly inhibit the secretion of inflammatory factors from immune cells; in an acute liver injury mouse model, they improve the survival rate of mice, reduce the transcription level of inflammatory factors in mouse liver tissue, improve liver tissue damage and reduce hepatocyte apoptosis; in a chronic liver injury mouse model, they reduce the expression of liver tissue fibrosis factors and the formation of liver tissue fibrous cords; they reduce the levels of liver enzymes ALT and AST, etc.; in a chronic acute-on-chronic liver failure mouse model, they significantly delay the peak of death of animals with chronic acute-on-chronic liver failure and increase the survival rate of animals, and improve liver and kidney blood flow disorders.
  • the present invention provides a method for preventing and/or treating liver damage diseases by targeted inhibition of p300/CBP in a subject in need thereof.
  • the targeted inhibition of p300/CBP includes targeting the HAT domain and BRD domain of p300/CBPp300p300.
  • the p300 treatment or prevention includes producing one or more of the following effects on the subject: inhibiting the secretion of inflammatory factors of immune cells, improving liver tissue damage, reducing hepatocyte apoptosis, lowering liver enzyme levels, improving liver and kidney blood flow disorders, and improving survival rate.
  • the targeted inhibition of p300/CBP comprises administering to the subject a therapeutically effective amount of a p300/CBP inhibitor, including but not limited to CCS1477, GNE207, NEO2734, A-485 and CBP30.
  • a p300/CBP inhibitor including but not limited to CCS1477, GNE207, NEO2734, A-485 and CBP30.
  • the liver injury disease includes acute liver injury, chronic liver injury and/or liver failure and acute-on-chronic liver failure.
  • the liver injury disease is acute liver injury
  • the dosage of the p300/CBP inhibitor administered to the subject is 20-40 mg/Kg for a single administration, for example, the dosage of the drug administered to the subject is 20 mg/Kg, 25 mg/Kg, 30 mg/Kg, 35 mg/Kg and 40 mg/Kg for a single administration.
  • the liver injury disease is chronic liver injury
  • the p300/CBP inhibitor is administered to the subject at a dose of 3-10 mg/Kg ⁇ day, such as 5 mg/Kg ⁇ day.
  • the liver injury disease is acute-on-chronic liver failure
  • the dosage of the p300/CBP inhibitor administered to the subject is 5-20 mg/Kg for a single administration, for example, the dosage of the drug administered to the subject is 5 mg/Kg, 10 mg/Kg, 15 mg/Kg and 20 mg/Kg for a single administration.
  • the present invention also provides a use of a p300/CBP inhibitor in the preparation of a medicament for preventing and/or treating liver damage diseases.
  • the p300/CBP inhibitor targets the HAT domain and the BRD domain of p300/CBP.
  • the liver injury disease includes acute liver injury, chronic liver injury and/or liver failure and acute-on-chronic liver failure.
  • the p300/CBP inhibitor includes but is not limited to CCS1477, GNE207, NEO2734, A-485 and CBP30.
  • the present invention further provides a drug for preventing and/or treating liver damage diseases, wherein the active ingredient of the drug comprises a p300/CBP inhibitor.
  • the p300/CBP inhibitor includes a compound targeting the HAT domain and the BRD domain of p300/CBP.
  • the p300/CBP inhibitor includes but is not limited to CCS1477, GNE207, NEO2734, A-485 and CBP30.
  • the liver injury disease includes acute liver injury, chronic liver injury and/or liver failure and acute-on-chronic liver failure.
  • the dosage form of the drug includes but is not limited to injection, tablet, capsule, oral granule, enema.
  • the drug of the present invention can be prepared into any drug dosage form that is convenient for administration.
  • the present invention also proposes a pharmaceutical composition for preventing and/or treating liver damage diseases, which comprises the drug described above and a pharmaceutically acceptable excipient, wherein the excipient is one or any combination selected from a binder, a filler, a coating polymer, a plasticizer, a glidant, a disintegrant and a lubricant.
  • CBP/p300 inhibitors are a class of epigenetic drugs that can inhibit the activity of CBP (CREB-binding protein) and p300 proteins, which play an important role in the transcription and expression regulation of inflammatory immune genes.
  • the inventors of the present application also unexpectedly discovered that when the p300/CBP inhibitor is selected from CCS1477, GNE207, NEO2734, A-485 and CBP30, especially when the p300/CBP inhibitor is CCS1477, it can effectively prevent or treat liver damage, successfully protect liver cells, reduce liver cell death caused by damage, reduce the release of inflammatory factors in immune cells, improve liver and kidney blood flow disorders, delay the peak of death of animals with chronic acute liver failure and improve the survival rate of individual animals.
  • the above-mentioned p300/CBP inhibitors proposed in the present invention are all small molecule compounds, which have low preparation, transportation and storage costs and are suitable for timely application when acute liver damage or failure and chronic acute liver failure occur.
  • the targeted inhibition of p300/CBP proposed in the present application can not only effectively solve the problem that there are no ideal drugs and therapeutic methods for acute-on-chronic liver failure, but also effectively prevent or treat liver damage diseases by inhibiting the secretion of inflammatory factors of individual immune cells, improving liver tissue damage, reducing hepatocyte apoptosis, reducing liver enzyme levels, and improving animal survival rate. Therefore, the method of targeted inhibition of p300/CBP proposed in the present application has broad market application prospects in the treatment of acute and chronic liver injury and/or liver failure and acute-on-chronic liver failure.
  • FIG1 is a comparison of mRNA levels of inflammatory factors in cells in a control group after LPS stimulation and a treatment group treated with different concentrations of p300/CBP inhibitors 2 hours before LPS stimulation according to Example 1 of the present invention.
  • Example 2 is a comparison chart of the protein levels of cellular inflammatory factors in a control group after LPS stimulation and a treatment group treated with different concentrations of p300/CBP inhibitors 2 hours before LPS stimulation according to Example 1 of the present invention.
  • Figure 3 is a comparison chart of the survival of mice in the LPS-induced acute liver failure model in mice according to Example 2 of the present invention, using a vehicle and LPS/D-GalN injection modeling group, a treatment group given a single intraperitoneal injection of CCS1477 4 hours before LPS/D-GalN injection, and a group only given a single intraperitoneal injection of CCS1477 to test drug toxicity.
  • Figure 4 is a comparison of the gross condition of liver tissues of mice in the LPS-induced acute liver failure model in mice, using the vehicle and LPS/D-GalN injection modeling groups and the treatment group given a single intraperitoneal injection of CCS1477 4 hours before LPS/D-GalN injection according to Example 2 of the present invention.
  • Figure 5 is a comparison of hematoxylin-eosin staining of liver tissues of mice in the LPS-induced acute liver failure model in mice according to Example 2 of the present invention, using the vehicle and LPS/D-GalN injection modeling group and the CCS1477 single intraperitoneal injection treatment group 4 hours before LPS/D-GalN injection.
  • Figure 6 is a comparison of TUNEL (terminal dexynucleotidyl transferase-mediated dUTP nick end labeling) apoptosis staining in liver tissue of mice in the LPS-induced acute liver failure model in mice, using the vehicle and LPS/D-GalN injection modeling groups and the treatment group given a single intraperitoneal injection of CCS1477 4 hours before LPS/D-GalN injection.
  • TUNEL terminal dexynucleotidyl transferase-mediated dUTP nick end labeling
  • Figure 7 is a comparison chart of serum biochemical indicators of hepatocyte damage: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the LPS-induced acute liver failure model in mice according to Example 2 of the present invention, including a vehicle and LPS/D-GalN injection modeling group, a single intraperitoneal injection treatment group of CCS1477 4 hours before LPS/D-GalN injection, and a single intraperitoneal injection of CCS1477 for drug toxicity detection.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • Figure 8 is a comparison of the mRNA levels of inflammatory factors in the liver tissue of mice in the LPS-induced acute liver failure model in mice according to Example 2 of the present invention, using solvent and LPS/D-GalN injection modeling groups and the treatment group given a single intraperitoneal injection of CCS1477 4 hours before LPS/D-GalN injection.
  • Figure 9 is a comparison of the gross conditions of liver tissues of mice in the vehicle control group, the CCl 4 injection modeling group, and the CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group in the CCl 4 induced chronic mouse liver fibrosis injury model according to Example 3 of the present invention.
  • Figure 10 is a comparison of Sirius red staining of liver tissue of mice in the vehicle control group, the CCl 4 injection modeling group and the CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group according to Example 3 of the present invention, in the CCl 4- induced chronic mouse liver fibrosis injury model.
  • Figure 11 is a comparison of ⁇ -SMA and Col1a1 staining of liver tissues of mice in the vehicle control group, the CCl 4 injection modeling group, and the CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group in the CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group according to Example 3 of the present invention.
  • Figure 12 is a comparison chart of serum biochemical indicators of hepatocellular injury: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in mice in the vehicle control group, the CCl 4 injection modeling group, and the CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group according to Example 3 of the present invention, in the CCl 4-induced chronic mouse liver fibrosis injury model.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • Figure 13 is a comparison chart of the mRNA levels of liver tissue fibrosis indicators in the CCl 4- induced chronic mouse liver fibrosis injury model according to Example 3 of the present invention, a solvent control group, a CCl 4 injection modeling group, and a CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group.
  • Figure 14 is a comparison chart of the liver tissue fibrosis index protein levels of mice in the CCl 4- induced chronic mouse liver fibrosis injury model according to Example 3 of the present invention, a solvent control group, a CCl 4 injection modeling group, and a CCl 4 injection modeling and CCS1477 intraperitoneal injection treatment group.
  • Figure 15 is a comparison of the survival of mice in the mouse acute-on-chronic liver failure model induced by CCl 4 and Klebsiella pneumoniae (KP) according to Example 4 of the present invention, and the modeling group and the treatment group given a single intraperitoneal injection of CCS1477, GNE207, and NEO2734 2 hours before KP injection.
  • Figure 16 is a comparison of laser Doppler blood flow imaging of the liver and kidneys of mice in the model of acute-on-chronic liver failure induced by CCl4 and Klebsiella pneumoniae (KP) in Example 4 of the present invention and the treatment group given a single intraperitoneal injection of CCS1477 2 hours before KP injection.
  • Figure 17 is a quantitative comparison of laser Doppler blood flow imaging of the liver and kidneys of mice in the model of acute-on-chronic liver failure induced by CCl4 and Klebsiella pneumoniae (KP) according to Example 4 of the present invention, and the modeling group and the treatment group given a single intraperitoneal injection of CCS1477 2 hours before KP injection.
  • the term "prevent” refers to a reduction in the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • treatment refers to any form of treatment that provides an effect including improvement of the individual's state (e.g., one or more symptoms), delay of disease progression, delay of symptom progression, or blunting of symptom progression, etc., to an individual who has a disease or is at risk of developing a disease. Therefore, the "treatment” and “prevention” do not refer to the cure or complete removal of symptoms.
  • RAW264.7 macrophages were seeded in 6-well plates with conditioned medium for 24 hours, and a control group, LPS model control group, and treatment group were set up.
  • the treatment groups used different p300/CBP inhibitors and set different concentrations.
  • the control group added the same dose of dimethyl sulfoxide solvent as the drug treatment group, and the LPS model control group and treatment group used 500ng/mL LPS to stimulate the cells for up to 6 hours.
  • the treatment group was given 2 hours before LPS stimulation, and then co-stimulated with LPS for 6 hours.
  • the trizol method was used to extract the cell RNA and perform real-time Fluorescence quantitative PCR experiments were performed to evaluate the mRNA expression levels of inflammatory factors TNF- ⁇ , IL-1 ⁇ , IFN ⁇ and NOS2 in each group of cells; or the cell supernatant was taken and enzyme-linked immunosorbent assay was performed to evaluate the protein expression levels of inflammatory factors TNF- ⁇ , IL-1 ⁇ and IL-6 in each group of cells.
  • Figure 1 shows the mRNA expression levels of inflammatory factors in the drug treatment group, blank control group and model control group after 6 hours of LPS stimulation.
  • Figure 2 shows the protein expression levels of inflammatory factors in the drug treatment group, blank control group and model control group after 6 hours of LPS stimulation.
  • A-485, CBP30 and CCS1477 in the treatment group can alleviate the increase in the expression level of inflammatory factors induced by LPS stimulation, and the therapeutic effect is concentration-dependent.
  • A-485 and CBP30 have similar efficacy, and both are weaker than CCS1477.
  • the groups were set up as model control group, drug treatment group, drug toxicity test group, and blank control group.
  • the experimental animals were 10-week-old, specific pathogen-free C57 male mice (to avoid the influence of estrogen).
  • the modeling scheme was a single intraperitoneal injection of 2mg/kg LPS (Lipopolysaccharide) combined with 250mg/kg D-GalN (D-galactosamine) dissolved in PBS.
  • the drug solvent is 10% DMSO (Dimethyl sulfoxide), 25-40% Peg300 (Polyethylene glycol 300), 65-50% PBS (Phosphate buffered saline).
  • the model control group was injected with the drug solvent 4 hours before LPS injection
  • the drug treatment group was injected with the drug solution 4 hours before LPS injection
  • the drug toxicity test group was injected with the drug solution 4 hours before PBS injection
  • the blank control group was injected with the drug solvent 4 hours before PBS injection.
  • the 24-hour survival rate of the mice in the observation group was observed: the number of deaths in each group was recorded 4 hours after LPS injection, and the number of deaths was recorded every 1 hour thereafter.
  • the mice in the sampling group were anesthetized 4 hours after LPS injection, their eyes were removed and blood was collected before being killed. The livers were then removed. Evaluation indicators: 24-hour survival rate, liver macroscopic appearance, liver function Evaluation: serum ALT and AST, pathological sections: HE staining, TUNEL apoptosis staining and transcription levels of inflammatory factors in liver tissue, etc.
  • Figure 3 shows the 24-hour survival rate of the model control group, drug treatment group (CCS1477, doses of 20 mg/kg and 40 mg/kg, respectively), drug toxicity detection group (CCS1477, dose of 40 mg/kg) and blank control group.
  • Figure 4 shows the gross appearance of the liver in the model control group, drug treatment group (CCS1477, 40 mg/kg) and blank control group.
  • Figure 5 shows the HE staining of liver tissue in the model control group, drug treatment group (CCS1477, 40 mg/kg) and blank control group.
  • Figure 6 shows the TUNEL apoptosis staining of liver tissue in the model control group, drug treatment group (CCS1477, 40 mg/kg) and blank control group.
  • Figure 7 shows the liver function evaluation indicators: serum ALT and AST in the model control group, drug treatment group (CCS1477, doses of 20 mg/kg and 40 mg/kg, respectively), drug toxicity detection group (CCS1477, dose of 40 mg/kg) and blank control group.
  • Figure 8 shows the transcription levels of inflammatory factors TNF ⁇ , IL-1 ⁇ , IL-6 and NOS2 in liver tissue of the model control group, drug treatment group (CCS1477, doses of 20 mg/kg and 40 mg/kg, respectively) and blank control group.
  • the 24-hour survival rate of mice in each group is shown in Figure 3: the 24-hour survival rate of mice in the model control group vs drug treatment group (CCS1477, 40 mg/kg) vs drug treatment group (CCS1477, 20 mg/kg) was (25% vs 83.33% vs 66.67%, p ⁇ 0.0001), and the 24-hour survival rate of mice in the drug toxicity group and the blank control group was 100%.
  • the gross appearance of the liver of mice in each group is shown in Figure 4: The morphology of the liver in the drug treatment group was significantly improved.
  • HE staining and TUNEL apoptosis staining of mice in each group are shown in Figures 5 and 6: HE staining of the liver tissue of mice in the model control group showed severe histological abnormalities, including destruction of liver tissue structure, hepatocyte necrosis, congestion and inflammatory cell infiltration.
  • mice were set up as model control group, drug treatment group and blank control group.
  • Experimental animals were selected as 6-8 weeks old, specific pathogen-free C57 male mice (to avoid the influence of estrogen).
  • the modeling scheme was that the model control group mice were intraperitoneally injected with 10% CCl 4 solution diluted with olive oil for 8 weeks, the injection frequency was twice a week, and the injection dose was 1mL/kg; the drug treatment group was given drug treatment at the same time from the week of injection of CCl 4 solution.
  • the drug treatment scheme was 5mg/kg ⁇ day CCS1477 prepared into a drug solution, intraperitoneally injected (100ul/mouse), and the drug solvent was 10% DMSO, 15% Peg300), 75% PBS; the blank control group was intraperitoneally injected for 8 weeks, and the corresponding dose of olive oil was twice a week.
  • the sampling time was 24 hours after the last CCl 4 injection and 4 hours after administration (fasting for 24h before sampling), blood was collected after anesthesia, and the liver was collected after sacrifice.
  • Evaluation indicators gross appearance of the liver, liver function evaluation: serum ALT and AST, pathological sections: Sirius red staining, immunohistochemical staining ( ⁇ -SMA and COL1A1) and transcription and protein levels of liver tissue fibrosis factors, etc.
  • Figure 9 shows the gross appearance of the liver in the model control group, drug treatment group (CCS1477, 5 mg/kg ⁇ day) and blank control group.
  • Figure 10 shows Sirius red staining of liver tissue in the model control group, drug treatment group (CCS1477, 5 mg/kg ⁇ day) and blank control group.
  • Figure 11 shows immunohistochemical staining ( ⁇ -SMA and COL1A1) in the model control group, drug treatment group (CCS1477, 5 mg/kg ⁇ day) and blank control group.
  • Figure 12 shows serum liver function evaluation indicators: ALT and AST levels in the model control group, drug treatment group (CCS1477, 5 mg/kg ⁇ day) and blank control group.
  • Figures 13 and 14 show the expression of fibrosis factors ( ⁇ -SMA and COL1A1) at the transcriptional level and protein level in the model control group, drug treatment group (CCS1477, 5 mg/kg ⁇ day) and blank control group, respectively.
  • Sirius red staining of the liver of mice in each group The results are shown in Figure 10: Sirius red staining of liver tissue of mice in the model control group showed deposition of fibers and collagen, and the degree of liver fibrosis increased, while the deposition of collagen in liver tissue and the degree of liver fibrosis in mice in the CCS1477 drug treatment group were significantly reduced.
  • the immunohistochemical staining ( ⁇ -SMA and COL1A1) of liver tissue of mice in each group is shown in Figure 11: The positive areas of ⁇ -SMA and COL1A1 increased significantly in the model control group, but decreased in the drug treatment group.
  • fibrosis factors ⁇ -SMA and COL1A1
  • Figures 13 and 14 Consistent with Figure 11, the expression of ⁇ -SMA and COL1A1 at the transcriptional and protein levels increased significantly in the model control group, but decreased in the drug treatment group.
  • the serum liver function evaluation indicators of mice in each group: ALT and AST levels are shown in Figure 12: The serum liver function evaluation indicators ALT and AST of mice increased significantly in the model control group, but were alleviated and reduced in the drug treatment group.
  • mice were set up as model control group and drug treatment group.
  • the experimental animals were 6-8 weeks old, specific pathogen-free C57 male mice (to avoid the influence of estrogen), and the modeling schemes were chronic modeling stage, acute attack stage and KP infection stage.
  • mice were intraperitoneally injected with 10% CCl 4 solution diluted in olive oil.
  • the injection time was 8-12 weeks, the injection frequency was twice a week, and the injection dose was 1mL/kg; the acute attack stage was 72 hours after the chronic modeling stage, and a single intraperitoneal injection of 10% CCl 4 solution diluted in olive oil was performed, and the injection dose was 2mL/kg; the KP infection stage was 24 hours after the acute attack stage, and a single intraperitoneal injection of KP bacterial solution was performed, with a concentration of 5000CFU/mL and a dose of 100uL/mouse.
  • the mice were treated with KP 2 hours before the KP injection.
  • the drug solvent was injected intraperitoneally once every 24 hours; the drug treatment group was injected intraperitoneally once 2 hours before KP injection after modeling, with a dose of 10 mg/kg, and the drug solvent was 10% DMSO, 25% Peg300, and 65% PBS.
  • Two groups were set up in parallel: the observation group and the blood flow observation group, that is, one group was used to observe the 72-hour survival rate; the other group was used to observe the blood flow of the liver and kidney.
  • the 72-hour survival rate of the mice in the observation group was observed: the number of deaths in each group was recorded 24 hours after the acute impact of CCl 4 injection, the number of deaths was recorded every 1 hour during the 24-48 hour period, and the number of deaths was recorded every 2 hours during the 48-72 hour period.
  • mice in the blood flow observation group were anesthetized and opened 48 hours after the acute impact of CCl 4 injection, and the other half were anesthetized and opened 60 hours after the acute impact of CCl 4 injection.
  • the liver and kidney blood flow were monitored by Doppler blood flow meter, and then the liver was removed. Evaluation indicators: 72-hour survival rate, liver and kidney blood flow, etc.
  • Figure 15 shows the 7-day survival rate of mice in the model control group and the drug treatment groups (CCS1477, 10 mg/kg), (NEO2734, 5 mg/kg), (GNE207, 10 mg/kg).
  • Figures 16 and 17 show the blood flow of the liver and kidneys of mice in the model control group and the drug treatment group (CCS1477, 10 mg/kg) under the laser Doppler monitoring instrument.
  • the 72-hour survival rate of mice in each group is shown in Figure 15: the 72-hour survival rate of mice in the model control group vs. the drug treatment group was (0.00% vs. 50.00%, p ⁇ 0.0001).
  • the liver and kidney blood flow conditions of mice in each group at 48 and 60 hours under Doppler blood flow monitoring are shown in Figures 16 and 17.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de l'inhibition ciblée de p300/CBP en traitement de maladies liées à une lésion hépatique et une méthode de prévention et/ou de traitement de maladies liées à une lésion hépatique par l'inhibition ciblée de p300/CBP chez un sujet qui en a besoin, les maladies liées à une lésion hépatique comprenant une lésion hépatique aiguë, une lésion hépatique et/ou insuffisance hépatique chronique et une insuffisance hépatique aiguë sur chronique. Un inhibiteur de p300/CBP présente de vastes perspectives d'application sur le marché dans le traitement d'une lésion hépatique et/ou insuffisance hépatique aiguë et chronique et d'une insuffisance hépatique aiguë sur chronique.
PCT/CN2023/135791 2023-12-01 2023-12-01 Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique Pending WO2025112027A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2023/135791 WO2025112027A1 (fr) 2023-12-01 2023-12-01 Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2023/135791 WO2025112027A1 (fr) 2023-12-01 2023-12-01 Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique

Publications (1)

Publication Number Publication Date
WO2025112027A1 true WO2025112027A1 (fr) 2025-06-05

Family

ID=95896127

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/135791 Pending WO2025112027A1 (fr) 2023-12-01 2023-12-01 Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique

Country Status (1)

Country Link
WO (1) WO2025112027A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110170052A (zh) * 2019-06-21 2019-08-27 复旦大学 Cbp-p300抑制剂在肠道损伤疾病中的应用
CN115006535A (zh) * 2022-04-19 2022-09-06 上海交通大学医学院附属瑞金医院 CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用
CN116942823A (zh) * 2023-06-19 2023-10-27 华中科技大学 Ep300作为靶点在制备治疗急性肝损伤药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110170052A (zh) * 2019-06-21 2019-08-27 复旦大学 Cbp-p300抑制剂在肠道损伤疾病中的应用
CN115006535A (zh) * 2022-04-19 2022-09-06 上海交通大学医学院附属瑞金医院 CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用
CN116942823A (zh) * 2023-06-19 2023-10-27 华中科技大学 Ep300作为靶点在制备治疗急性肝损伤药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PENG, JINJIN: "The Protective Effect and Mechanism of P300/CBP HAT Inhibitor A485 on ALI", CHINESE MASTER'S THESES FULL-TEXT DATABASE, MEDICINE AND HEALTH SCINECES, 15 June 2020 (2020-06-15), XP093319449 *
VAN GILS NOORTJE, MARTIAÑEZ CANALES TANIA, VERMUE ELINE, RUTTEN ARJO, DENKERS FEDOR, VAN DER DEURE TIEM, OSSENKOPPELE GERT J., GIL: "The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells", HEMASPHERE, WOLTERS KLUWER HEALTH, US, vol. 5, no. 8, US , pages e610, XP093319446, ISSN: 2572-9241, DOI: 10.1097/HS9.0000000000000610 *
WU, JUN: "Recent Advances in Inhibitors of Histone Acetyltransferase p300/CBP", PROGRESS IN PHARMACEUTICAL SCIENCES, vol. 43, no. 2, 1 January 2019 (2019-01-01), pages 118 - 126, XP093319447 *

Similar Documents

Publication Publication Date Title
Cai et al. ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway
JP6954698B2 (ja) テトラメチルピラジンニトロン誘導体の糖尿病合併症疾患の予防と治療における応用
WO2005082349A1 (fr) Composition de traitement de l'obesite contenant un derive de fumagillol
WO2008122190A1 (fr) Composition comprenant de la l-carnitine ou ses dérivés et son utilisation
IL261669B1 (en) A combination of thyroid hormones and a rxr agonist for the treatment of autoimmune diseases
CN118831081A (zh) 吲哚乙酸在制备治疗肝纤维化药物中的用途
KR20100014267A (ko) Ａｃａｔ 억제제 및 이의 섬유증 예방 또는 치료에서의 용도
EP2606883B1 (fr) Utilisations de n-butylidenephthalide dans le traitement d'une lésion du foie et amélioration de la fonction hépatique
JP2024504555A (ja) 急性膵炎を予防及び治療するための薬物の製造におけるノルハルマンの使用
WO2025112027A1 (fr) Utilisation de l'inhibition ciblée de p300/cbp en traitement de maladies liées à une lésion hépatique
CN118903111A (zh) 吲哚在制备治疗肝纤维化药物中的用途
CN119424436A (zh) 化合物rociletinib通过抑制铁死亡在制备急性肝损伤的药物中的应用
CN104736151A (zh) 纤维化的柚皮素和积雪草酸组合治疗
CN116115760A (zh) Eed抑制剂在制备治疗神经免疫性疾病药物中的应用
CN115778944A (zh) 蛇床子素在制备改善或治疗认知功能障碍的药物中的用途
WO2006015546A1 (fr) Utilisation de bicyclol pour produire un medicament capable de prevenir et/ou traiter l’alcoolisme aigu et une lesion d’intestin d’alcoolisme aigu ou chronique
CN117045629B (zh) 地骨皮甲素在治疗肾结石药物中的用途
CN115300501B (zh) Tpt-260在制备用于治疗脑卒中的药物中的应用
CN118121593B (zh) 一种用于预防和/或治疗阿尔茨海默病的药物组合物及其用途
CN113908161A (zh) 钩吻素子用于治疗脓毒症的用途
CN112023027B (zh) 胸腺素或其衍生物的应用和治疗快感缺乏型抑郁症的药物
CN114522235B (zh) Bcar3抑制剂及其在预防和治疗纤维化疾病中的用途
CN119868383B (zh) 桑皮苷a在制备预防和治疗肺纤维化疾病的药物中的应用
CN110384705B (zh) 山楂酸在制备治疗2型糖尿病胰岛细胞损伤药物中的应用
CN118717780A (zh) 土大黄苷在制备防治类风湿关节炎的药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23959937

Country of ref document: EP

Kind code of ref document: A1