At concentrations up to 100 μM for 48 hours, SB-505124 shows no toxicity to renal epithelial A498 cells. With an IC50 value of 129±11 nM, which is approximately 2.5 times less sensitive than ALK5, 505124 inhibits the closely related ALK4, but not ALK2, even at concentrations up to 10 μM. In all three of these cell lines, SB-505124 (1 μM) inhibits the TGF-β-induced phosphorylation of Smad2 in a concentration-dependent manner. Even though these cells exhibit distinct patterns of activation, SB-505124 (1 or 5 μM) effectively suppresses TGF-β-induced activation of JNK/SAP, extracellular signal-regulated kinase 1/2, and p38[1]. In vitro, SB-505124 (10 µM) inhibits the phosphorylation of Smad2, as well as the expression of CTGF and α-SMA. By using immunofluorescence, SB-505124 is able to suppress CTGF and α-SMA. While cell outgrowth is poor from eyes treated with MMC, it is robust from explants dissected from eyes to which SB-505124 is applied during GFS[3].

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The gel was characterized for in vitro drug release and viscosity studies. Cytotoxicity of Pluronic® F-127 was examined by MTT assay using cultured rabbit subconjunctival fibroblasts. The in vitro drug release study demonstrated 100% drug release within 12 h. The gel did not show cytotoxicity to the cultured rabbit subconjunctival cells by MTT assay. [2]

In C57Bl6 mice bearing A549 xenografts, SB-505124 (5 mg/kg; i.p.) by itself showed no impact; however, when combined with a single carboplatin dose (60 mg/kg), SB-505124 caused long-lasting responses in five species, eliminating the need for maintenance therapy [4].

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The purpose of this study is to investigate a thermoreversible gel using Pluronic® F-127 to deliver an activin receptor-like kinase 5 (ALK-5) inhibitor SB-505124 in glaucoma filtration surgery (GFS). In addition, Pluronic® F-127 gel (18% w/v) containing 5 mg of SB-505124 was applied at the surgical site in an in vivo rabbit GFS model. In the in vitro viscosity study, the gel showed a change in viscosity (from 1000 cps to 45,000 cps) from low temperature (10°C) to body temperature (37°C). In the in vivo rabbit GFS model, the drug was successfully delivered by injection and no severe post-surgical complications were observed. A thermoreversible gel system with SB-505124 was successfully prepared and delivered for the rabbit GFS model, and it may provide a novel delivery system in GFS.[2]

Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542[1].

Animal/Disease Models: C57Bl6 mice with A549 xenografts [4]
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection; Daily
Experimental Results: No effect alone, but a single dose of carboplatin (60 mg/kg) gave The drug produced durable responses in 5 animals, requiring no maintenance treatment.

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In an in vivo rabbit GFS model, SB-505124 was delivered in a lactose tablet during surgery. Eyes were examined by slit-lamp and intraocular pressure (IOP) was measured until the time of bleb failure or up to 28 days after surgery. Tissue sections on day 5 after surgery were histologically evaluated after staining with hematoxylin and eosin. The sections were also immunostained for CTGF and α-SMA.[3]

[1]. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2004 Mar;65(3):744-52.

[2]. Thermoreversible gel for delivery of receptor-like kinase 5 inhibitor SB-505124 for glaucoma filtration surgery. Pharm Dev Technol. 2013 Jul-Aug;18(4):957-62.

[3]. Suppression of transforming growth factor-β effects in rabbit subconjunctival fibroblasts by receptor-like kinase 5 inhibitor. Mol Vis. 2010 Sep 16;16:1880-92.

[4]. Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. Sci Transl Med. 2018 Jul 25;10(451). pii: eaat3504.

Purpose: Transforming growth factor-β (TGF-β) activity has been implicated in subconjunctival scarring in eyes following glaucoma filtration surgery (GFS). The purpose of this study is to determine whether an inhibitor for activin receptor-like kinase (ALK) 5 (also known as TGF-β receptor type I) could suppress TGF-β activity and thereby promote filtering bleb survival after GFS in a rabbit model. Results: The docking study indicated hydrogen bond interactions between SB-505124 and amino acids His-283 and Ser-280 of ALK-5. Suppression of pSmad2, CTGF, and α-SMA by SB-505124 was observed in cultured fibroblasts. Filtering blebs in the GFS with SB-505124 group were maintained for more than 10 days, and the period of bleb survival was significantly longer than that in controls. IOP levels after surgery seemed to be related to bleb survival. Histologically, subconjunctival cell infiltration and scarring at the surgical site in the GFS with SB-505124 and mitomycin C (MMC) groups were much subsided compared to controls. Suppression of CTGF and α-SMA by SB-505124 was also observed by immunofluorescence. Cell outgrowth from explants dissected from eyes to which SB-505124 was applied during GFS was robust while outgrowth was poor from those treated with MMC. Conclusions: The ALK-5 inhibitor SB-505124 was efficacious both in vitro and in vivo in suppressing the TGF-β action. The inhibitor may provide a novel therapy for preventing ocular inflammation and scarring.[3]

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Resistance to platinum chemotherapy is a long-standing problem in the management of lung adenocarcinoma. Using a whole-genome synthetic lethal RNA interference screen, we identified activin signaling as a critical mediator of innate platinum resistance. The transforming growth factor-β (TGFβ) superfamily ligands activin A and growth differentiation factor 11 (GDF11) mediated resistance via their cognate receptors through TGFβ-activated kinase 1 (TAK1), rather than through the SMAD family of transcription factors. Inhibition of activin receptor signaling or blockade of activin A and GDF11 by the endogenous protein follistatin overcame this resistance. Consistent with the role of activin signaling in acute renal injury, both therapeutic interventions attenuated acute cisplatin-induced nephrotoxicity, its major dose-limiting side effect. This cancer-specific enhancement of platinum-induced cell death has the potential to dramatically improve the safety and efficacy of chemotherapy in lung cancer patients.[4]

C20H22CLN3O2

371.860583782196

371.14

C, 64.60; H, 5.96; Cl, 9.53; N, 11.30; O, 8.60

356559-13-2

SB-505124;694433-59-5

16079009

Light yellow to green yellow solid powder

5.275

2

4

3

26

466

0

BTUOOXPZOVNPMF-UHFFFAOYSA-N

InChI=1S/C20H21N3O2.ClH/c1-12-6-5-7-14(21-12)18-17(22-19(23-18)20(2,3)4)13-8-9-15-16(10-13)25-11-24-15;/h5-10H,11H2,1-4H3,(H,22,23);1H

2-[4-(1,3-benzodioxol-5-yl)-2-tert-butyl-1H-imidazol-5-yl]-6-methylpyridine;hydrochloride

SB-505124 hydrochloride; SB-505124 (hydrochloride); SB-505124 HCl; CHEMBL1824446; 356559-13-2 (HCl); 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3h-imidazol-4-yl)-6-methylpyridine hydrochloride; SB505124 hydrochloride;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

MEthanol : ~125 mg/mL (~336.15 mM)
DMSO : ~50 mg/mL (~134.46 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.72 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 25.0 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.)