SB-505124 hydrochloride

SB505124 is a selective inhibitor of TGFβR for ALK4, ALK5 with IC50 value of 129 nM and 47 nM [1].

Anaplastic lymphoma kinase (ALK) gets involved in the development of the brain and influence specific neurons in the nervous system.

SB505124 is a reversible ATP competitive inhibitor of ALK4 and ALK5. Incubation of the ALK5 with high concentrations of SB505124, followed by dilution to a sub-IC50 concentration resulted in no effect of downstream Smad3 phosphorylation [2]. SB505124 was shown to have no toxicity to renal epithelial A498 cells at concentrations up to 100 μM for 48 h. Evidence showed that 100% drug will release within 12 h, and the gel showed no cytotoxicity to the cultured rabbit subconjunctival cells[2]. It was observed that ALK4 downstream effectors including pSmad2, CTGF, and α-SMA was inhibited by SB505124 in cultured fibroblasts [3].

In rabbit in glaucoma filtration surgery (GFS) model, the period of filtering blebs were reduced by TGFβ induced fibroblast. The filtering blebs in the GFS with SB505124 group were maintained for more than 10 days, and the period of bleb survival was significantly longer than that in controls, which suggested the significant inhibition of ALK4 and 5 by SB505124 [2]. It was observed that ALK4 downstream effectors CTGF and α-SMA were suppressed by SB-505124 in vivo[3].

References:
[1].  DaCosta B S et al. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol., 2004,65(3): 744-52.
[2].  Sutariya V, et al. Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor SB-505124 for glaucoma filtration surgery. Pharm Dev Technol., 2013, 18(4): 957-962.
[3].  Sapitro J, et al. Suppression of transforming growth factor-β effects in rabbit subconjunctival fibroblasts by activin receptor-like kinase 5 inhibitor. Mol Vis., 2010, 16: 1880-1892.

Transforming growth factor-beta stimulates Smad1/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1.[Pubmed:28642261]

Am J Physiol Lung Cell Mol Physiol. 2017 Sep 1;313(3):L615-L627.

The intracellular signaling mechanisms through which TGF-beta regulates pulmonary development are incompletely understood. Canonical TGF-beta signaling involves Smad2/3 phosphorylation, Smad2/3.Smad4 complex formation and nuclear localization, and gene regulation. Here, we show that physiologically relevant TGF-beta1 levels also stimulate Smad1/5 phosphorylation, which is typically a mediator of bone morphogenetic protein (BMP) signaling, in mouse pup pulmonary artery smooth muscle cells (mPASMC) and lung fibroblasts and other interstitial lung cell lines. This cross-talk mechanism likely has in vivo relevance because mixed Smad1/5/8.Smad2/3 complexes, which are indicative of TGF-beta-stimulated Smad1/5 activation, were detected in the developing mouse lung using a proximity ligation assay. Although mixed Smad complexes have been shown not to transduce nuclear signaling, we determined that TGF-beta stimulates nuclear localization of phosphorylated Smad1/5 and induces the expression of prototypical BMP-regulated genes in the mPASMC. Small-molecule kinase inhibitor studies suggested that TGF-beta-regulated Smad1/5 phosphorylation in these cells is mediated by TGF-beta-type I receptors, not BMP-type I receptors, but possibly the accessory activin-like kinase (ALK1) receptor. Although work by others suggested that ALK1 is expressed exclusively in endothelial cells in the vasculature, we detected ALK1 mRNA and protein expression in mPASMC in vitro and in mouse pup lungs. Moreover, using an antimurine ALK1 antibody and mPASMC, we determined that ALK1 regulates Smad1/5 phosphorylation by TGF-beta. Together, these studies characterize an accessory TGF-beta-stimulated BMP R-Smad signaling mechanism in interstitial cells of the developing lung. They also indicate the importance of considering alternate Smad pathways in studies directed at determining how TGF-beta regulates newborn lung development.

Development and validation of an LC-MS/MS method for the determination of SB-505124 in rat plasma: Application to pharmacokinetic study.[Pubmed:26363490]

J Pharm Biomed Anal. 2016 Jan 5;117:205-9.

A sensitive, selective and rapid liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) method has been developed for the quantification of the novel transforming growth factor-beta (TGF-beta) inhibitor SB-505124 in rat plasma and then validated. Plasma samples were prepared by simple protein precipitation. Separation was performed on a Diamonsil ODS chromatography column using a mobile phase of acetonitrile and 0.1% (v/v) aqueous formic acid. SB-505124 and the internal standard doxorubicin were detected in the positive ion mode using multiple reaction monitoring of the transitions at m/z 336.2-->320.1 and 544.2-->397.2, respectively. Calibration curve was linear (r>0.9996) over a concentration range of 10-5000 ng/mL with the lower quantification limit of 10 ng/mL. Both intra- and inter-day precision were within 6.5% and trueness were not more than 3.1%. Extraction recovery and matrix effect were within acceptable limits. Stability tests showed that SB-505124 and the IS remained stable throughout the analytical procedure. The validated LC-MS/MS method was then used to analyze the pharmacokinetics of SB-505124 administered to rats intravenously (8 mg/kg) or orally (10 mg/kg). Oral bioavailability of SB-505124 was calculated as 76.4%, indicating the potential of SB-505124 as an orally administered drug.

Autocrine TGF-beta/ZEB/microRNA-200 signal transduction drives epithelial-mesenchymal transition: Kinetic models predict minimal drug dose to inhibit metastasis.[Pubmed:27000495]

Cell Signal. 2016 Aug;28(8):861-70.

The epithelial-mesenchymal transition (EMT) is the crucial step that cancer cells must pass before they can undergo metastasis. The transition requires the activity of complex functional networks that downregulate properties of the epithelial phenotype and upregulate characteristics of the mesenchymal phenotype. The networks frequently include reciprocal repressions between transcription factors (TFs) driving the EMT and microRNAs (miRs) inducing the reverse process, termed mesenchymal-epithelial transition (MET). In this work we develop four kinetic models that are based on experimental data and hypotheses describing how autocrine transforming growth factor-beta (TGF-beta) signal transduction induces and maintains an EMT by upregulating the TFs ZEB1 and ZEB2 which repress the expression of the miR-200b/c family members. After successful model calibration we validate our models by predicting requirements for the maintenance of the mesenchymal steady state which agree with experimental data. Finally, we apply our validated kinetic models for the design of experiments in cancer therapy. We demonstrate how steady state properties of the kinetic models, combined with data from tumor-derived cell lines of individual patients, can predict the minimal amount of an inhibitor to induce a MET.

Delayed ALK5 inhibition improves functional recovery in neonatal brain injury.[Pubmed:26984936]

J Cereb Blood Flow Metab. 2017 Mar;37(3):787-800.

Neuroinflammation subsequent to developmental brain injury contributes to a wave of secondary neurodegeneration and to reactive astrogliosis that can inhibit oligodendrocyte progenitor differentiation and subsequent myelination. Here we evaluated the therapeutic efficacy of a small molecule antagonist for a TGFss receptor in a model of moderate perinatal hypoxia-ischemia (H-I). Osmotic pumps containing SB505124, an antagonist of the type 1 TGFss1 receptor ALK5, or vehicle, were implanted three days after H-I induced at postnatal day 6. Perinatal H-I induced selective neuronal death, ventriculomegaly, elevated CNS levels of IL-6 and IL-1alpha, astrogliosis, and fewer proliferating oligodendrocyte progenitors. Myelination was reduced by approximately 50%. Anterograde tracing revealed extensive axonal loss in the corticospinal tract. These alterations correlated with functional impairments across a battery of behavioral tests. All of these parameters were brought back towards normal levels with SB505124 treatment. Notably, SB505124 preserved neurons in the hippocampus and thalamus. Our results indicate that inhibiting ALK5 signaling, even as late as three days after injury, creates an environment that is more permissive for oligodendrocyte maturation and myelination producing significant improvements in neurological outcome. This new therapeutic would be especially appropriate for moderately preterm asphyxiated infants, for whom there is presently no FDA approved neuroprotective therapeutic.

Staurosporine induces chondrogenesis of chick embryo wing bud mesenchyme in monolayer cultures through canonical and non-canonical TGF-beta pathways.[Pubmed:26427712]

In Vitro Cell Dev Biol Anim. 2016 Jan;52(1):120-9.

Staurosporine has been known to induce chondrogenesis in monolayer cultures of mesenchymal cells by dissolving actin stress fibers. The aim of this study was to further elucidate how the alteration of actin filaments by staurosporine induces chondrogenesis. Specifically, we examined whether the transforming growth factor (TGF)-beta pathway is implicated. SB505124 strongly suppressed staurosporine-induced chondrogenesis without affecting the drug's action on the actin cytoskeleton. Staurosporine increased the phosphorylation of TGF-beta receptor I (TbetaRI) but had no significant effect on the expression levels of TGF-beta1, TGF-beta2, TGF-beta3, TbetaRI, TbetaRII, and TbetaRIII. Phosphorylation of Smad2 and Smad3 was not increased by staurosporine. However, SB505124 almost completely suppressed the phosphorylation of Smad2 and Smad3. In addition, inhibition of Smad3 blocked staurosporine-induced chondrogenesis. Inhibition of Akt, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) suppressed chondrogenesis induced by staurosporine. Phosphorylation of Akt, p38 MAPK, and JNK was increased by staurosporine. SB505124 reduced the phosphorylation of Akt and p38 MAPK, while it had no effect on the phosphorylation of JNK. The phosphorylation level of extracellular signal-regulated kinase (ERK) was not significantly affected by staurosporine. In addition, inhibition of ERK with PD98059 alone did not induce chondrogenesis. Taken together, these results suggest that staurosporine induces chondrogenesis through TGF-beta pathways including canonical Smads and non-canonical Akt and p38 MAPK signaling.

SB-505124 hydrochloride is a selective inhibitor of TGF-β Receptor type I receptor (ALK4, ALK5, ALK7), with IC50s of 129 nM and 47 nM for ALK4, ALK5, respectively, but it does not inhibit ALK1, 2, 3, or 6.

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