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SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice.

Park JH, Ryu SH, Choi EK, Ahn SD, Park E, Choi KC, Lee SW - Oncotarget (2015)

Bottom Line: SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro.In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction.Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

ABSTRACT
Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.

No MeSH data available.


Related in: MedlinePlus

Concentration-dependent effects of SKI2162 on ALK5 inhibitionThe inhibition of ALK5 activity by SKI2162 and LY2157299 was tested using purified recombinant ALK5. Different concentrations of each test compound were used and percent-activity values were calculated to derive the corresponding IC50 values. The calculated IC50 values for SKI2162 and LY2157299 were 0.094 μM and 0.327 μM, respectively.
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Figure 1: Concentration-dependent effects of SKI2162 on ALK5 inhibitionThe inhibition of ALK5 activity by SKI2162 and LY2157299 was tested using purified recombinant ALK5. Different concentrations of each test compound were used and percent-activity values were calculated to derive the corresponding IC50 values. The calculated IC50 values for SKI2162 and LY2157299 were 0.094 μM and 0.327 μM, respectively.

Mentions: The result of assays for inhibitory and selectivity effects of SKI2162 on ALK5 are shown in Figure 1 and Supplementary Table 1. The IC50 values for SKI2162 and LY2157299 were 0.094 μM and 0.327 μM, respectively, demonstrating that SKI2162 was approximately 3-fold more potent than LY2157299 in inhibiting ALK5 activity. Selectivity assays of SKI2162 and LY2157299 indicated that SKI2162 was 21-fold more selective for ALK5 inhibition than p38 MAPK inhibition, whereas LY2157299 did not discriminate between ALK5 and p38 MAPK. Both SKI2162 and LY2157299 showed 73-fold and 40-fold higher selectivity for ALK5 than ALK1, respectively.


SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice.

Park JH, Ryu SH, Choi EK, Ahn SD, Park E, Choi KC, Lee SW - Oncotarget (2015)

Concentration-dependent effects of SKI2162 on ALK5 inhibitionThe inhibition of ALK5 activity by SKI2162 and LY2157299 was tested using purified recombinant ALK5. Different concentrations of each test compound were used and percent-activity values were calculated to derive the corresponding IC50 values. The calculated IC50 values for SKI2162 and LY2157299 were 0.094 μM and 0.327 μM, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414180&req=5

Figure 1: Concentration-dependent effects of SKI2162 on ALK5 inhibitionThe inhibition of ALK5 activity by SKI2162 and LY2157299 was tested using purified recombinant ALK5. Different concentrations of each test compound were used and percent-activity values were calculated to derive the corresponding IC50 values. The calculated IC50 values for SKI2162 and LY2157299 were 0.094 μM and 0.327 μM, respectively.
Mentions: The result of assays for inhibitory and selectivity effects of SKI2162 on ALK5 are shown in Figure 1 and Supplementary Table 1. The IC50 values for SKI2162 and LY2157299 were 0.094 μM and 0.327 μM, respectively, demonstrating that SKI2162 was approximately 3-fold more potent than LY2157299 in inhibiting ALK5 activity. Selectivity assays of SKI2162 and LY2157299 indicated that SKI2162 was 21-fold more selective for ALK5 inhibition than p38 MAPK inhibition, whereas LY2157299 did not discriminate between ALK5 and p38 MAPK. Both SKI2162 and LY2157299 showed 73-fold and 40-fold higher selectivity for ALK5 than ALK1, respectively.

Bottom Line: SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro.In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction.Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

ABSTRACT
Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.

No MeSH data available.


Related in: MedlinePlus