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KR-20260066436-A - COMPOSITION FOR PREVENTING OR TREATING RENAL DISEASES COMPRISING TRAMETINIB

KR20260066436AKR 20260066436 AKR20260066436 AKR 20260066436AKR-20260066436-A

Abstract

The present invention relates to a composition for preventing, improving, or treating kidney disease comprising trametanib as an active ingredient, which can treat cisplatin-induced renal failure by reducing inflammation, oxidative stress, and tubular cell death.

Inventors

  • 임재찬
  • 김정연

Assignees

  • 대구가톨릭대학교산학협력단

Dates

Publication Date
20260512
Application Date
20241104

Claims (6)

  1. A pharmaceutical composition for the prevention or treatment of kidney disease, comprising trametinib as an active ingredient.
  2. In Article 1, A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the kidney disease is renal failure.
  3. In Article 1, A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the kidney disease is cisplatin-derived acute renal failure.
  4. In Article 1, The above trametinib is a pharmaceutical composition for the prevention or treatment of kidney disease that reduces inflammation, oxidative stress, and tubular cell death.
  5. A food composition for preventing or improving kidney disease, comprising trametinib as an active ingredient.
  6. A health functional food composition for preventing or improving kidney disease, comprising trametinib as an active ingredient.

Description

Composition for preventing or treating renal diseases comprising trametinib The present invention relates to a pharmaceutical composition for the prevention or treatment of kidney disease comprising trametinib as an active ingredient. Cisplatin, a platinum-containing chemotherapy agent, is widely used to treat various solid tumors. Despite its usefulness in cancer treatment, cisplatin has the drawback of nephrotoxicity, which can cause acute renal failure (AKI) and potentially lead to long-term renal impairment. While the development of therapeutic strategies to mitigate cisplatin-induced nephrotoxicity is essential, limitations on the optimal dosage and duration of treatment can affect the overall efficacy of the therapy regimen. Cisplatin-induced nephrotoxicity is primarily caused by inflammation, oxidative stress, and tubular cell death. The inflammatory process is initiated when cisplatin induces the release of cytokines and damage-related molecular patterns, leading immune cells such as macrophages to attack the kidney. These cells further exacerbate damage through the release of pro-inflammatory mediators. Additionally, the entry of cisplatin into kidney cells and its subsequent metabolic response can generate reactive oxygen species (ROS), causing significant oxidative damage and potentially worsening kidney injury. This oxidative stress is a key factor in the apoptosis observed in tubular epithelial cells, characterized by mitochondrial dysfunction and the activation of cell death pathways. Recent studies have highlighted the development of alternative cell death mechanisms, such as necrotosis, ferroptosis, and pyroptosis, in the progression of nephrotoxicity. The extracellular signal-regulated kinase (ERK) pathway is one of the important signaling cascades in the mitogen-activated protein kinase (MAPK) family. Activation of the ERK pathway typically begins at the cell surface where growth factors bind to receptor tyrosine kinases. This binding initiates a cascade involving the phosphorylation of MAP kinase kinase 1/2 (MEK1/2) and the subsequent activation of ERK1/2. This pathway is involved in various cellular processes, including inflammation, oxidative stress, and cell death, and has been identified as a cause of cisplatin-induced nephrotoxicity. In particular, the ERK pathway inhibitor U0126 demonstrated a protective effect against cisplatin-induced AKI by reducing inflammation and apoptosis. Drug repurposing, which identifies new therapeutic uses for existing drugs, can significantly reduce development costs and time. Trametinib, a potential and selective MEK1/2 inhibitor, is an FDA-approved drug that has been proven effective in the treatment of advanced or metastatic melanoma with specific B-Raf proto-oncogene (BRAF) mutations (Flaherty, K.T. et al., N. Engl. J. Med. 2012, 367, 107-114). Its biological activity involves inhibiting MEK1/2 and preventing the activation of ERK1/2, thereby disrupting downstream signaling pathways critical for cell proliferation and survival. Clinically, trametinib is being extensively studied in combination with other targeted drugs, such as dabrafenib, to increase the efficacy of treating BRAF-mutated melanoma (Chung, C. et al., Am. J. Health Syst. Pharm. 2015, 72, 101-110). These studies have demonstrated increased overall survival and progression-free survival in patients. However, trametinib has several side effects, such as rash, diarrhea, and lymphedema, as well as serious adverse events such as cardiomyopathy and retinal vein occlusion. Figure 1 shows the effects of trametinib on the MEK-ERK pathway and renal function in cisplatin-infused mice: (A) Western blot results of p-MEK and p-ERK in renal tissue. (B) Bar graph showing quantified band densities of p-MEK and p-ERK (normalized to total protein levels (n = 6 per group)). (C) Serum creatinine levels (n = 8 per group). (D) BUN levels (n = 8 per group). Data are presented as standard ± SEM. * p < 0.05 and *** p < 0.001 vs. Con. ## p < 0.01 and ### p < 0.001 vs. CP. Figure 2 shows the effect of trametinib on histopathological malformations in cisplatin-injected mice: (A) Representative image of H&E or PAS-stained kidney sections. Scale bar = 100 μm. Red arrows indicate tubular dilation, and blue arrows indicate cast deposition in the tubular cystic cavity. (B) Tubular damage score (n = 8 per group). Data are presented as standard ± SEM. * p < 0.05 and *** p < 0.001 versus Con. ### p < 0.001 versus CP. Figure 3 shows the effect of trametinib on the expression of tubular injury markers KIM-1 and NGAL in cisplatin-infused mice: (A) Representative image of IHC staining for KIM-1. Scale bar = 100 μm. (B) Quantitative analysis of KIM-1 positive staining (n = 8 per group). (C) Western blot results for NGAL in kidney tissue. (D) Bar graph showing the quantified band density of NGAL (normalized to GAPDH levels) (n = 6 per group). Data are presented as standard ± SEM. *** p < 0.001 versus Con. ### p < 0.001 versus C