Belumosudil (KD025)

製品コードS7936 バッチS793602

印刷

化学情報

Chemical Structure Synonyms SLx-2119 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C26H24N6O2
分子量 452.51 CAS No. 911417-87-3
Solubility (25°C)* 体外 DMSO 90 mg/mL (198.89 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Belumosudil (KD025, SLx-2119) is an orally available, and selective ROCK2 inhibitor with IC50 and Ki of 60 nM and 41 nM, respectively. Phase 2.
in vitro

KD025 down-regulates the IL-17 and IL-21 secretion in human PBMCs, and leads to down-regulation of STAT3 phosphorylation, IRF4, and RORγt expression in CD4+ T cells. [2]

KD025 inhibits the secretion of IL-21, IL-17, and IFNγ along with decreasing phosphorylated STAT3 and reduced protein expression of IRF4 and BCL6 in human peripheral blood mononuclear cells. [3]
in vivo

In mice, KD025 (200 mg/kg, p.o.) inhibits ROCK activity in brain and heart, as measured by the degree of MYPT1 phosphorylation. KD025 (200 mg/kg, p.o.) significantly reduces the area of perfusion defect, and reduces tissue loss in the ipsilateral hemisphere. [1]

In a collagen-induced arthritis (CIA) mouse model, KD025 (200 mg/kg, i.p.) downregulates the progression of collagen-induced arthritis via targeting of the Th17-mediated pathway. [2]

KD025 ()150 mg/kg, i.p. or p.o.) effectively ameliorates cGVHD in a full MHC-mismatch model of multi-organ system cGVHD with bronchiolitis obliterans syndrome and a minor MHC-mismatch model of sclerodermatous GVHD. [3]

プロトコル(参考用のみ)

キナーゼアッセイ Recombinant ROCK1 and ROCK2 assays
Compound dilutions and reactions are performed in 96-well polystyrene low-binding plates. Filtration is done in 96-well filter plates containing hydrophilic phospho-cellulose cation exchanger membranes. Enzymatic activity of the recombinant ROCK1 and ROCK2 is measured radiometrically in 50 μL of reaction mixture containing assay buffer (50 mmol/L Tris, pH 7.5, 0.1 mmol/L ethyleneglycoltetraacetic acid, 10 mmol/L magnesium acetate and 1 mmol/L dithiothreitol). Long S6 peptide (KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK, 30 μmol/L), ROCK (4 mU per reaction) and ATP (10 μmol/L; 1 μCi [[gamma]-33P]ATP) and test compound are diluted to a final dimethylsulfoxide concentration of 1%. The reaction is incubated for 45 min at room temperature and stopped with 25 μL of 3% phosphoric acid. Phosphorylated long S6 peptide is separated from unreacted [[gamma]-33P]ATP by filtration of the quenched reaction contents through a P30 phosphocellulose filter plate. Each filter is washed three times with 75 μL of 75 mmol/L phosphoric acid and one time with 30 μL of 100% methanol. Filter plates are allowed to dry and 30 μL of OptiPhase ‘SuperMix’ scintillation fluid is added to each well. 33Phosphorous is quantified in an I450 MicroBeta scintillation counter and corrected by subtracting the radioactivity associated with the background samples. Data are analyzed and expressed as percent inhibition using the formula ((U − B)/(C − B)) × 100 where U is the unknown value, B is the average of staurosporine background wells, and C is the average of control wells. Curve fitting is performed by GraphPad Prism software using sigmoidal dose-response (variable slope) equation type analysis to generate IC50 values. Ki values are calculated from an equation of Ki = IC50/(1 + [S]/Km)), where [S] and Km are the concentration of ATP and the Km value of ATP, respectively.
細胞アッセイ 細胞株 A7r5 cells
濃度 10 µM
反応時間 2 h
実験の流れ

Cells were treated with KD025 for 2 hours.
動物実験 動物モデル Young adult, aged, or type 2 diabetic mice
投薬量 300 mg/kg
投与方法 p.o.

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism [ Commun Biol, 2023, 10.1038/s42003-023-05552-0] PubMed: 37980369
ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation [ Nat Commun, 2022, 13(1):703] PubMed: 35121738
Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3 [ Clin Transl Med, 2022, 12(10):e1036] PubMed: 36178087
Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity [ ACS Chem Biol, 2022, 10.1021/acschembio.2c00052] PubMed: 35439415
Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching [ Sci Adv, 2022, 8(15):eabm3471] PubMed: 35427166
The Rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension [ Biochem Biophys Res Commun, 2021, 534:795-801] PubMed: 33160621
Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B-cell lymphoma [ Sci Rep, 2020, 10(1):13094] PubMed: 32753663
KD025, an anti-adipocyte differentiation drug, enhances the efficacy of conventional chemotherapeutic drugs in ABCG2-overexpressing leukemia cells [ Oncol Lett, 2020, 20(6):309] PubMed: 33093918
Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma. [ Sci Signal, 2018, 11(557)] PubMed: 30459283

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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