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
- Gareth J. Inman1,
- Francisco J. Nicolás1,
- James F. Callahan2,
- John D. Harling3,
- Laramie M. Gaster4,
- Alastair D. Reith5,
- Nicholas J. Laping6 and
- Caroline S. Hill1
- 1Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK (G.J.I., F.J.N., C.S.H.); 2Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania (J.F.C.);3Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, Stevenage, Hertfordshire, UK (J.D.H.); 4Department of High-Throughput Chemistry (L.M.G.) and 5High-Throughput Biology (A.D.R.), GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK; and 6Renal and Urology Research, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (N.J.L.)
- Dr. Caroline Hill, Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. E-mail: caroline.hill{at}cancer.org.uk
Abstract
Small molecule inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction pathways whose activities contribute to human diseases. Transforming growth factor β (TGF-β) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-β superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases. Here, we characterize a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-β type I receptor). We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains. It has no effect on the other, more divergent ALK family members that recognize bone morphogenetic proteins (BMPs). Consistent with this, we demonstrate that SB-431542 is a selective inhibitor of endogenous activin and TGF-β signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum.
Footnotes
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This work was funded by Imperial Cancer Research Fund (now Cancer Research UK after the merger of Imperial Cancer Research Fund with the Cancer Research Campaign), GlaxoSmithKline Pharmaceuticals, and a Medical Research Council training fellowship (to F.J.N.).
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G.J.I. and F.J.N. contributed equally to this work.
- Abbreviations:
- TGF-β
- transforming growth factor β
- BMP
- bone morphogenetic protein
- AMH
- anti-Müllerian hormone
- ALK
- activin receptor-like kinase
- SB-431542
- 4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide
- DE
- distal element
- OP
- operator
- SRF
- serum response factor
- FCS
- fetal calf serum
- BSA
- bovine serum albumin
- EGF
- epidermal growth factor
- DMEM
- Dulbecco's modified Eagle's medium
- DMSO
- dimethyl sulfoxide
- GRB2
- growth-factor receptor-bound protein 2
- ATF
- activating transcription factor
- SRE
- serum response element
- β-Gal
- β-galactosidase
- GS
- glycine- and serine-rich
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- Received November 28, 2001.
- Accepted March 21, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
