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 to block renal fibrogenesis induced by unilateral ureteral obstruction (UUO) in rats. Either vehicle (saline) or IN-1130 (10 and 20 mg/kg/day) was intraperitoneally administered to UUO rats for 7 and 14 days. Phosphorylated Smad2 (pSmad2) and markers of fibrosis were analyzed in kidney tissues. In UUO control kidneys, interstitial fibrosis including tubular atrophy, loss and dilation, inflammatory cell infiltration, and fibroblast cell proliferation was prominent. These morphological changes were notably reduced by IN-1130 treatment. IN-1130 decreased levels of TGF-beta1 messenger RNA (mRNA), type I collagen mRNA, and pSmad2, compared to UUO control rats. As determined by measuring the hydroxyproline content, total kidney collagen amount was increased in UUO control kidneys, but significantly reduced by IN-1130 treatment, which was comparable to results of histochemical staining for collagen. IN-1130 also suppressed the expression of alpha-smooth muscle actin (alpha-SMA) and fibronectin in UUO kidneys. Our results show that IN-1130 suppressed the fibrogenic process of UUO, further underscoring the potential clinical benefits of IN-1130 in the treatment of renal fibrosis.[1]

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TGF-β signaling plays an important role in breast cancer progression and metastasis. Epithelial-mesenchymal transition (EMT) is an important step in the progression of solid tumors to metastatic disease. We previously reported that IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppressed renal fibrosis in obstructive nephropathy (Moon et al., 2006). Here, we show that IN-1130 suppressed EMT and the lung metastasis of mammary tumors in mouse models. Treating human and mouse cell lines with IN-1130 inhibited TGF-β-mediated transcriptional activation, the phosphorylation and nuclear translocation of Smad2, and TGF-β-induced-EMT, which induces morphological changes in epithelial cells. Additionally, we demonstrated that IN-1130 blocked TGF-β-induced 4T1 mammary cancer cell migration and invasion. The TGF-β-mediated increase in matrix metalloproteinase (MMP)-2 and MMP-9 expression was restored by IN-1130 co-treatment with TGF-β in human epithelial cells and in 4T1 cells. Furthermore, we found that lung metastasis from primary breast cancer was inhibited by IN-1130 in both 4T1-xenografted BALB/c mice and MMTV/c-Neu transgenic mice without any change in primary tumor volume. IN-1130 prolonged the life span of tumor-bearing mice. In summary, this study indicated that IN-1130 has therapeutic potential for preventing breast cancer metastasis to the lung.[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.)