Introduction: Inhibitors of ALK

Activin receptor like-kinases (ALK1) are defined as being a type 1 receptor specifically for the transforming growth factor ß (TGF-ß) family of proteins. It is recorded that ALK1 expression is found in blood vessels and may be linked to vascular formation. Since tumor growth is dependant on generating a vascular skeleton to support itself ALK1 appears to be a potential target for chemotherapeutic action. Analysis of hereditary hemorrhagic telangiectasia disorders revealed a mutation n the ALK1 gene transcription [1]. ALK is encoded by ALK gene and plays an important role in the development of brain function. Fusion of the ALK gene with other genes such as the nucleophosmin gene or the EML4 gene is can be linked to specifc types of carcinomas. In NSCLC the EML4- ALK fusion is theroised to be the driving force behind the tumor. Inhibition of the ALK, therefore presents itself forward a potential target for chemotherapy. This is confirmed by the EML4-ALK inhibitor Crizotinib which has achieved approval for use in NSCLC patients. Potentially SB-431542 is another small molecule which could make a huge impact since the SB-431542 IC50 has been determined to be 94nM for ALK5, it remains to be determined whether this can be translated into a sucessfuly chemotherapy agent.

SB 431542 Chemical Structure

SB-431542: Properties and availability:

SB-431542 JAK inhibitor was discovered and is currently marketed by GlaxoSmithKline for translational research purposes. SB-431542 structure clearly indicates that it is a tri substituted pyrimidine with activity for 3 of the known ligands of the activin receptor like kinases (ALK). The SB-431542 IC50 for its targets are ALK 4 (3.3 nM), ALK 5 ( ) and ALK 7 (2.8 nM), but SB-431542 has also been shown to be active against Tyk2 (19 nM) and JAK 3 (323 nM) [2]. SB-431542 solubility in water is extremely poor but SB-431542 is soluble in DMSO and ethanol, with maximum concentrations of 77 mg/ml and 45 mg/ml being achievable respectively. SB-431542 stability is listed for its powdered form only and this can be stored for upwards of 2 years if kept at -20oC. The stock solutions this product carries the recommendation to be protected from light. Researchers can buy SB-431542 from a limited number of SB-431542 suppliers although SB-431542 price is dependent on the supplier. The price of a 10 mg vial can range from $110 up to $150.


SB-431542: Preclinical investigations

SB-431542 is currently used as a research aid for the investigation of the activin receptor like pathway. SB-431541 is marketed as a selective inhibitor of ALK´s 4,5&7 and evidences pre-clinically demonstrates this to be accurate.[3;4] However, SB-431542 has been researched inconjuction with other kinases and has been found to inhibit several other kinases as well as ALK 4,5&7 [5]. While SB-431542 is not as selective as previously believe it still plays an important role in the unlocking of the mechanisms of action of the transforming growth factor (TGF)-beta. SB-431542 has been established to have no effect on bone morphogenetic protein (BMP). SB-431542 was tested on endothelial cells to investigated the communication between VEGF and TGF-ß, it was observed that VEGF and SB-431542 up regulated angiogenesis synergistically. SB-431542 also inhibited TGFß downstream of which is the Smad3 proteins, the MAPK pathway and extracellular signal regulated pathway. It was observed to inhibit phosphorylation of Smad3 proteins many of the TGF-ß regulated processes [6]. In glioma cells SB-431542 was seen to halt invasion, cell transformations and growth .[7;8] In human cell that are groeth inhibited by TFGß SB-431542 has been observed to induce the growth of cells, increase invasion and cell motility. Hence tumors that are resistant to TGFß induced suppressor SB-431542 is able to inhibit tumor invasion, angiogenesis and metastasis.[9]

SB-431542: Clinical Status

SB-431542 has not been utilized in the clinical setting with relation to cancers. The potential for promoting tumor growth is too a risk. Instead SB-431542 has been used clinically in relation to a series of other disorders such as Chagas disease where TGFß inhibition appears to decrease muscle injury thereby preventing heart damage. [10] In all the most significant clinical response to the SB-431542 inhibitor is to induce cellular growth, this aids such processes as wound healing offering a potential clinical use for this type of inhibitor.[11;12]


   1.   Oh SP, Seki T et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 2000; 97(6):2626-2631.

   2.   Shilling AD, Nedza FM et al. Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans. Drug Metab Dispos 2010; 38(11):2023-2031.

   3.   DaCosta BS, Major C 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):744-752.

   4.   Inman GJ, Nicolas FJ et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002; 62(1):65-74.

   5.   Vogt J, Traynor R et al. The specificities of small molecule inhibitors of the TGFss and BMP pathways. Cell Signal 2011; 23(11):1831-1842.

   6.   Galvin KM, Donovan MJ et al. A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 2000; 24(2):171-174.

   7.   Hjelmeland MD, Hjelmeland AB et al. SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol Cancer Ther 2004; 3(6):737-745.

   8.   Lu Y, Jiang F et al. TGF-beta1 promotes motility and invasiveness of glioma cells through activation of ADAM17. Oncol Rep 2011; 25(5):1329-1335.

   9.   Halder SK, Beauchamp RD et al. A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia 2005; 7(5):509-521.

10.   Waghabi MC, de Souza EM et al. Pharmacological inhibition of transforming growth factor beta signaling decreases infection and prevents heart damage in acute Chagas' disease. Antimicrob Agents Chemother 2009; 53(11):4694-4701.

11.   Cabello-Verrugio C, Cordova G et al. Connective tissue growth factor induction by lysophosphatidic acid requires transactivation of transforming growth factor type beta receptors and the JNK pathway. Cell Signal 2011; 23(2):449-457.

12.   Sugiyama K, Ishii G et al. Improvement of the breaking strength of wound by combined treatment with recombinant human G-CSF, recombinant human M-CSF, and a TGF-beta1 receptor kinase inhibitor in rat skin. Cancer Sci 2008; 99(5):1021-1028.

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S1067 SB431542 SB431542 is a potent and selective inhibitor of ALK5 with IC50 of 94 nM in a cell-free assay, 100-fold more selective for ALK5 than p38 MAPK and other kinases.

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