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CN-121971616-A - Medicine for treating bosutinib hepatotoxicity by taking CAMK2G gene or protein as target spot

CN121971616ACN 121971616 ACN121971616 ACN 121971616ACN-121971616-A

Abstract

The invention discloses a medicine for treating bosutinib hepatotoxicity by taking a CAMK2G gene or protein as a target spot, and belongs to the technical field of medicines. The medicament relieves the liver toxicity of bosutinib by down regulating the expression of the CAMK2G gene or restoring the phosphorylation of the CAMK2G protein. The invention discloses that the CAMK2G gene is a key gene of liver injury and abnormal glucose metabolism caused by bosutinib, and provides a novel prevention and treatment target for intervention of hepatotoxicity caused by bosutinib. The invention provides a new direction for searching an intervention strategy of hepatotoxicity caused by medicines by restoring CAMK2G phosphorylation and relieving liver injury and abnormal glycometabolism by using a CAMK2G phosphorylation activator, and solves the current situation of few clinically available intervention medicines and single mechanism to a certain extent.

Inventors

  • LUO PEIHUA
  • YAN HAO
  • HE QIAOJUN
  • YANG BO
  • XU ZHIFEI
  • CAO YASHI

Assignees

  • 浙江大学

Dates

Publication Date
20260505
Application Date
20260203

Claims (10)

  1. 1. Application of a substance for targeted inhibition of CAMK2G gene expression or restoration of CAMK2G protein phosphorylation level in preparation of drugs for treating bosutinib hepatotoxicity.
  2. 2. The use according to claim 1, wherein the bosutinib hepatotoxicity is triggered by the bosutinib causing endoplasmic reticulum stress in the liver.
  3. 3. The use according to claim 1 or 2, wherein the manifestations of bosutinib hepatotoxicity include liver injury, abnormal glycolipid metabolism.
  4. 4. The use of claim 1, wherein the agent is an siRNA or shRNA that down-regulates CAMK2G gene expression in hepatocytes.
  5. 5. The method of claim 4, wherein the siRNA has a nucleotide sequence of 5'-CCACAGAAGAUGAGGACCUUU-3'.
  6. 6. The use according to claim 1, wherein the substance is a CAMK2G protein phosphorylation activator or an endoplasmic reticulum stress inhibitor.
  7. 7. The use of claim 6, wherein the activator of CAMK2G protein phosphorylation is SAK3 and the endoplasmic reticulum stress inhibitor is 4-phenylbutyric acid.
  8. 8. An anti-tumor combined pharmaceutical composition is characterized by comprising a first preparation consisting of bosutinib and a pharmaceutically acceptable carrier, and a second preparation consisting of SAK3 and a pharmaceutically acceptable carrier.
  9. 9. The pharmaceutical composition of claim 8, wherein the mass ratio of bosutinib to SAK3 is 2000:3.
  10. 10. Use of a pharmaceutical composition according to claim 8 or 9 for the preparation of a medicament for the treatment of chronic myeloid leukemia.

Description

Medicine for treating bosutinib hepatotoxicity by taking CAMK2G gene or protein as target spot Technical Field The invention relates to the technical field of medicines, in particular to an application of a CAMK2G gene or a CAMK2G protein as a medicine intervention target in preparing a medicine for treating bosutinib hepatotoxicity. Background Bosutinib (Bosutinib, SKI-606) is a breakpoint cluster region-Ai Buer-fusion gene (Breakpoint Cluster Region-Abelson fusion gene, BCR-ABL) tyrosine kinase inhibitor (Tyrosine kinase inhibitor, TKI), and has been approved for first-line treatment of chronic, accelerated and rapid-onset stages of chronic myelogenous leukemia (Chronic myeloid leukemia, CML), with significant efficacy in CML patients with resistance and intolerance to prior therapies such as imatinib. Although bosutinib exhibits good therapeutic effects in clinical applications, it brings about serious hepatotoxicity and attracts more and more attention. Multiple randomized controlled clinical trials (e.g., BFORE, ASCEMB and BYOND studies) showed that elevated serum alanine aminotransferase (alanine aminotransferase, ALT) and aspartate aminotransferase (ASPARTATE AMINOTRANSFERASE, AST) were common in both primary and postline treatments, with rates of 21-63% and 16-49%, respectively, and even 1 patient died due to severe hepatotoxicity （Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood. 2021;138(21):2031-2041.）. At present, the clinic lacks specific intervention means, and usually only drug stopping or drug reducing measures can be adopted, which can definitely delay the treatment process of tumor patients, thereby influencing the survival prognosis of the tumor patients. Therefore, it is currently a more urgent need to provide new prophylactic and therapeutic targets for bosutinib-induced hepatotoxicity. Calmodulin-dependent protein kinase II gamma (Calcium/calmodulin dependent protein KINASE II GAMMA, CAMK G) is specifically expressed in the liver and has an important regulatory role in Calcium signal transduction and cellular stress response. It has been reported that targeting liver CAMK2G and downstream thereof or substrates thereof can significantly enhance the phosphorylation levels of Akt in palmitic acid treated hepatocytes and the liver of obese mice, thereby improving metabolic index （Ozcan L, Cristina de Souza J, Harari AA, Backs J, Olson EN, Tabas I. Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metab. 2013;18(6):803-815.）., but no literature report exists on the relationship between the phosphorylation level of CAMK2G protein and the liver toxicity of bosutinib at present, and further study is required. The pre-clinical medicine SAK3 is a powerful T-type Ca 2+ channel enhancer and specifically targets Cav3.1 and Cav3.3 subtype. Studies have shown that SAK3 is effective in improving cognitive function and promoting neurogenesis by activating CAMK2G in animal models of neurodegenerative diseases （Yabuki Y, Matsuo K, Izumi H, et al. Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer. Neuropharmacology. 2017;117:1-13.）. SAK3 has not been reported to be useful in the treatment of liver diseases, particularly drug-induced liver injury. Disclosure of Invention The invention aims at solving the problems of toxic and side effects of the liver in the administration of the bosutinib and expanding the clinical application value of the bosutinib by exploring the gene/protein related to the liver toxicity induced by the bosutinib and taking the gene/protein as an action target for preventing and treating the liver toxicity of the bosutinib and screening the medicine for treating the liver toxicity side effects of the bosutinib. In order to achieve the above purpose, the invention adopts the following technical scheme: the invention provides application of a substance for targeted inhibition of CAMK2G gene expression or restoration of CAMK2G protein phosphorylation level in preparation of a drug for treating bosutinib hepatotoxicity. Further, the bosutinib hepatotoxicity is triggered by the occurrence of endoplasmic reticulum stress of the liver caused by bosutinib. Further, the manifestations of bosutinib hepatotoxicity include liver injury, abnormal glycolipid metabolism. Specifically, inflammatory infiltration of liver cells, accumulation of lipid droplets, elevation of liver weight ratio, elevation of serum alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) levels, reduction of liver tolerance to glucose, elevation of blood sugar, elevation of serum insulin, total Cholesterol (TC) and Triglyceride (TG) levels. The research of the invention discovers that the effect of the bosutinib can induce the hepatic parenchymal cells to generate endoplasmic reticu