SB-431542 – MEDIATES ALK INHIBITION

by Selleckchem | Mar 20 2012

ALK (ANAPLASTIC LYMPHOMA KINASE) RECEPTOR:

Anaplastic lymphoma kinase or ALK is encoded by ALK gene and it is also called as CD246 (Cluster of Differentiation-246). This kinase is famous for the brain development but by the genetic fusion of any other gene it can be an oncogenic gene, another reason for its genetic variability is due to the normally found mutations of DNA. In case of ALCLs or large cell lymphomas, NPM (nucleophosmin) is present in fusion form with ALK and this is responsible for the 60% of this cancer. In some of the other cancers like NSCLC (non-small cell lung cancer) and most of adenocarcinomas, the ALK-EML4 fused genes are found as the main cause of tumor formation. Similarly in a pediatric cancer that is known as neuroblastoma, mutated ALK is reported as the main reason in various studies. All of these important examples enlighten the significance of this pathway in different cancers and tumors therefore the discovery or development of such compounds which inhibit the ALK TKs pathway is important. Certain approved inhibitors like Crizotinib used for lung cancer treatment enhances the uses of different inhibitors found in inhibitor library including SB-431542 ALK inhibitor.

SB 431542 Chemical Structure

SB-431542 PHARMACOLOGICAL STUDIES:

There are different types of the ALK that is activin receptor like kinase. SB-431542 IC50 used for the selective and effective ALK inhibition is 94 nM. Therefore SB-431542 can be effective against various ALKs including ALK4, ALK7 and ALK5 which is a receptor of TGF-β (transforming growth factor-β) type I [1]. SB-431542 is available for research purposes and laboratory usage that is developed by GSK (Glaxo Smith Kline) and is available from any SB-431542 supplier. For a vial of 10 mg, SB-431542 price is $80 so this inhibitor is easy to buy from any of the supplier. SB-431542 solubility is like some other inhibitors is good in organic solvent DMSO and ethanol for a 100mM and 10 mM solutions respectively. For long time duration storage low temperature is suitable however the room temperature can also be used for short term storage to ensureSB-431542 stability.

SB-431542 PRECLINICAL TESTING AND CLINICAL USE:

Smad3 phosphorylation as well as its nuclear translocation was also blocked by SB-431542. It was also checked the mRNA of fibronectin (FN) that is activated by the TGFb1 and it is also reported that it inhibited collagen Ia1 induced by TGFb1 [2]. A similar results were reported during in vitro studies of gliomas models, nuclear translocation and phosphorylation of SMADs was checked by SB-431542, the intracellular signaling mediators (TGFβ) levels were also decreased, and the transcription of VEGF mediated by TGFβ along with plasminogen activator inhibitor-1 were also blocked by SB-431542 this further inhibited the propagation, invasion and morphological transformation of gliomal cells [3]. It was also found that SB-431542 inhibited the transcription induced by TGFβ, secretion of VEGF, growth suppression, gene expression, cell motility, migration, invasion, property of colony formation for anchorage independent growth and apoptosis in cancer cell lines of human [4]. TGF-β induced induce growth stimulation was also blocked by SB-431542 and thereby confirming its function in human oesteosarcoma cells proliferation [5].

SB-431542 is also used in some of the conditions other than cancers. In this context one of the examples is of its usage in cardiomyocytes and epithelial cells pharmacological treatment for the Chagas disease. Another example is of T. cruzi infection in which TGF-β signaling pathway is found as an important for cell cycle regulation and SB-431542 targets this pathway therefore reducing the cardiomyocyte invasion to diminish the amount of parasites per cell; this is a reasonable approach to check trypomastigote release and differentiation [6]. Contraction of fibroblasts induced by TGF-β is also found as checked by SB-431542 during a study in which the effect of this inhibitor was analyzed in a keloid and normal fibroblasts due to suppression of TGF-b signaling, this shows the potential of SB-431542 for therapy of excessive skin contractions as in keloid conditions [7]. More recently SB-431542 is patented for the eye treatment and other conditions of wound healing.

REFERENCES:

1. Inman GJ, e.a., SB-431542 Is a Potent and Specific Inhibitor of Transforming Growth Factor-β Superfamily Type I Activin Receptor-Like Kinase (ALK) Receptors ALK4, ALK5, and ALK7. Molecular Pharmacology, 2002.

2. Laping NJ, e.a., Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol., 2002.

3. Hjelmeland MD, e.a., SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility.Mol Cancer Ther, 2004.

4. Halder SK, e.a., A Specific Inhibitor of TGF-β Receptor Kinase, SB-431542, as a Potent Antitumor Agent for Human Cancers. Neoplasia, 2005.

5. Matsuyama S, e.a., SB-431542 and Gleevec Inhibit Transforming Growth Factor-β-Induced Proliferation of Human Osteosarcoma Cells. Cancer Res, 2003.

6. Waghabi MC, e.a., SB-431542, a Transforming Growth Factor β Inhibitor, Impairs Trypanosoma cruzi Infection in Cardiomyocytes and Parasite Cycle Completion.Antimicrob. Agents Chemother., 2007.

7. Hasegawa T, e.a., SB-431542 inhibits TGF-β-induced contraction of collagen gel by normal and keloid fibroblasts. Journal of Dermatological Science, 2005.