ALK5/transforming growth factor-β type I receptor kinase

In HepG2 and 4T1 cells, IN-1130 (0.5, 1 μM; 2 hours) suppresses TGF-β-stimulated Smad2 phosphorylation and additive nuclear translocation [2]. IN-1130 (1 μM; for 72 hours) suppresses TGF-β-induced MMPs mRNA production and the gelatin-opsonizing activity of apoptotic MMPs in MCF10A cells, while also restoring TGF [2]. 1130 (1 μM; 30 minutes of rest) suppresses the migration and model of MDA-MB-231, NMuMG, and MCF10A cells induced by TGF-β [2].

IN-1130 (10, 20 mg/kg/day; i.p.; for 7 and 14 days) reduced the degree of interstitial nephritis and fibrosis (arrow) at 10 mg/kg and considerably at 20 mg/kg or the lack of urinary histological alterations associated with unilateral ductal obstruction (UUO) [1]. IN-1130 (10, 20 mg/kg/day; for 14 days) dose-decreased stability of TGF-β1 mRNA in UUO kidney IN-1130 (40 mg/kg; i.p.; 3 times weekly for 3 weeks ) in MMTV/c-Neu mice (

The transforming growth factor-beta (TGF-beta) plays a central role in the progression of renal fibrosis. TGF-beta transduces its signal through the activin receptor-like kinase (ALK)5. IN-1130, a novel small molecule ALK5 inhibitor, inhibited the purified kinase domain of ALK5-mediated Smad3 phosphorylation with an IC(50) value of 5.3 nM. IN-1130 proved to be highly selective in a panel of 27 serine/threonine and tyrosine kinases including p38alpha mitogen-activated protein kinase[1].

Western Blot analysis [2]
Cell Types: HepG2 and 4T1 cells
Tested Concentrations: 0.5, 1 μM
Incubation Duration: 2 hrs (hours)
Experimental Results: Inhibition of TGF-β-stimulated Smad2 phosphorylation.

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RT-PCR[2]
Cell Types: MCF10A Cell
Tested Concentrations: 1 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: Inhibited TGF-β-induced MMPs mRNA expression and gelatinolytic activity of secreted MMPs.

Animal/Disease Models: Sixweeks old male SD (SD (Sprague-Dawley)) rats, body weight 180-200 g [1]
Doses: 10 and 20 mg/kg
Route of Administration: IP; daily; 7 days and 14-day
Experimental Results: 10 mg/kg diminished the extent of interstitial nephritis and fibrosis (arrow).

[1]. IN-1130, a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int. 2006 Oct;70(7):1234-43.

[2]. An novel inhibitor of TGF-β type I receptor, IN-1130, blocks breast cancer lung metastasis through inhibition of epithelial-mesenchymal transition. Cancer Lett. 2014 Aug 28;351(1):72-80.

Researchers evaluated the efficacy of IN-1130 in inhibiting unilateral ureteral obstruction (UUO)-induced renal fibrosis in rats. UUO rats were intraperitoneally injected with either a carrier (saline) or IN-1130 (10 and 20 mg/kg/day) for 7 and 14 days. The levels of phosphorylated Smad2 (pSmad2) and fibrosis markers in renal tissue were analyzed. In the UUO control kidneys, interstitial fibrosis was prominent, including tubular atrophy, loss and dilation, inflammatory cell infiltration, and fibroblast proliferation. IN-1130 treatment significantly reduced these morphological changes. Compared to the UUO control rats, IN-1130 reduced the levels of TGF-β1 mRNA, type I collagen mRNA, and pSmad2. By measuring hydroxyproline content, we found that the total collagen content in the kidneys of the UUO control group was increased, while IN-1130 treatment significantly reduced the total collagen content, consistent with the results of collagen histochemical staining. IN-1130 also inhibited the expression of α-smooth muscle actin (α-SMA) and fibronectin in the kidneys of UUO. Our results suggest that IN-1130 inhibits the fibrotic process in UUO, further highlighting the potential clinical benefit of IN-1130 in the treatment of renal fibrosis. [1]

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The TGF-β signaling pathway plays an important role in the progression and metastasis of breast cancer. Epithelial-mesenchymal transition (EMT) is an important step in the progression of solid tumors to metastatic disease. We previously reported that the novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor IN-1130 can inhibit renal fibrosis in obstructive nephropathy (Moon et al., 2006). In this paper, we found that IN-1130 can inhibit epithelial-mesenchymal transition (EMT) and lung metastasis of breast tumors in a mouse model. Treatment of human and mouse cell lines with IN-1130 inhibited TGF-β-mediated transcriptional activation, Smad2 phosphorylation and nuclear translocation, as well as TGF-β-induced EMT (which causes changes in epithelial cell morphology). In addition, we confirmed that IN-1130 blocked TGF-β-induced migration and invasion of 4T1 breast cancer cells. In human epithelial cells and 4T1 cells, combined treatment with IN-1130 and TGF-β restored the increase in TGF-β-mediated matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, we found that IN-1130 inhibited primary breast cancer lung metastasis in 4T1 xenografted BALB/c mice and MMTV/c-Neu transgenic mice without affecting the primary tumor volume. IN-1130 prolonged the lifespan of tumor-bearing mice. In conclusion, this study shows that IN-1130 has therapeutic potential for preventing lung metastasis of breast cancer. [2]

C25H20N6O

420.48

420.17

868612-83-3

11676119

White to light yellow solid powder

4.964

2

5

5

32

646

0

RYKSGWSKILPDDY-UHFFFAOYSA-N

InChI=1S/C25H20N6O/c1-15-4-2-7-20(29-15)24-23(17-8-9-19-21(14-17)28-11-10-27-19)30-22(31-24)13-16-5-3-6-18(12-16)25(26)32/h2-12,14H,13H2,1H3,(H2,26,32)(H,30,31)

3-[[5-(6-methylpyridin-2-yl)-4-quinoxalin-6-yl-1H-imidazol-2-yl]methyl]benzamide

IN 1130; IN1130; Benzamide, 3-((4-(6-methyl-2-pyridinyl)-5-(6-quinoxalinyl)-1H-imidazol-2-yl)methyl)-; CHEMBL492634; KW4O83PQ97; 3-((5-(6-Methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl) methyl)benzamide; IN-1130

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~237.83 mM)

Solubility in Formulation 1: ≥ 1.43 mg/mL (3.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)