Belumosudil (KD025) is a selective inhibitor of ROCK2 with IC50s of 105 nM and 24 µM for ROCK2 and ROCK1, respectively.
体内研究
Administration of Belumosudil (KD-025; doses of 100, 200, or 300mg/kg, intraperitoneally) results in a dose-proportional diminution of infarct size post-transient middle cerebral artery obstruction. Moreover, Belumosudil demonstrates comparable effectiveness in aged, diabetic, or female mice to that observed in standard adult male subjects[2].
体外研究
Belumosudil (40 µM) elicits notable suppressions of Tsp-1 and CTGF mRNA concentrations in PASMC. Hybridization of the microarray with aRNA from HMVEC, following Belumosudil treatment, displays a quintuple increase in background compared to other arrays[1].
Belumosudil 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human CD4+ T cells
0.1, 0.5, 1, 2.5, 5, 10 µM
1 hour
KD025 down-regulated the secretion of IL-21 and IL-17 in a dose-dependent manner in vitro, with a lesser effect on IFN-γ secretion.
Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16814-9.
Human CD4+ T cells
10 µM
1 hour
KD025 treatment significantly reduced the binding of STAT3 and RNA pII to the promoters of IL-21 and IL-17.
Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16814-9.
Bone marrow-derived macrophages (BMDM)
10 µM
20 minutes
To investigate the effect of Belumosudil on IL-17-induced STAT3 phosphorylation, results showed that Belumosudil significantly inhibited IL-17-induced STAT3 phosphorylation.
JHEP Rep. 2021 Oct 6;4(1):100386.
SLE CD4+ T cells
90 µM
4 days
To evaluate the effect of Y27632 on IL-17 and IL-21 production by SLE CD4+ T cells, results showed that Y27632 significantly inhibited the production of IL-17 and IL-21.
Ann Rheum Dis. 2017 Apr;76(4):740-747.
Human umbilical cord CD4+ T cells
90 µM
4 days
To evaluate the effect of Y27632 on IL-17A and IL-21 production by human umbilical cord CD4+ T cells, results showed that Y27632 significantly inhibited the production of IL-17A and IL-21.
Ann Rheum Dis. 2017 Apr;76(4):740-747.
SW1353 cells
2.5 µM
KD025 significantly downregulated the expression levels of MMP3 and MMP13 and promoted ACAN expression in SW1353 cells, indicating its role in alleviating cartilage degeneration by enhancing FUNDC1-PFKP interaction and mitophagy
Mol Ther. 2023 Dec 6;31(12):3594-3612.
Primary Human Chondrocytes (PHCs)
2.5 µM
KD025 significantly decreased the mRNA expression of MMP3, MMP13, and ADAMTS5, but upregulated ACAN expression in PHCs, indicating its role in alleviating cartilage degeneration by enhancing FUNDC1-PFKP interaction and mitophagy
Mol Ther. 2023 Dec 6;31(12):3594-3612.
Belumosudil 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
DMM-induced osteoarthritis model
Oral
100 mg/kg
Once daily for 4 weeks
KD025 significantly alleviated DMM-induced osteoarthritis and cartilage degeneration by enhancing FUNDC1-PFKP interaction and mitophagy
Mol Ther. 2023 Dec 6;31(12):3594-3612.
Mice
Thioacetamide (TAA)-induced liver fibrosis model
Oral gavage
100 mg/kg/day
Once daily for 1 week or 6 weeks
To investigate the prophylactic and therapeutic effects of Belumosudil on TAA-induced liver fibrosis, results showed that Belumosudil significantly attenuated liver fibrosis and promoted fibrotic regression.
JHEP Rep. 2021 Oct 6;4(1):100386.
Mice
Collagen-induced arthritis model
Intraperitoneal injection
50, 100, 200 mg/kg
Once daily for 28 days
KD025 treatment markedly down-regulated the progression of inflammatory arthritis and reduced the infiltration of immune cells in joints.
Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16814-9.
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