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Type I Receptors ALK4, ALK5, and ALK7
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland (S.A.D.B., C.M., A.B.R.); and Departments of Renal and Urology Research, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (N.J.L.)
Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-
) and/or modulate effects of TGF- in normal responses. Inhibition of TGF- signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF- 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- 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-–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- action, as evidenced by its ability to abrogate cell death caused by TGF-1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.
Received June 13, 2003; accepted December 12, 2003.
Address correspondence to: Dr. Anita B. Roberts, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bldg. 41, Rm C629, 41 Library Drive, MSC 5055, Bethesda, MD 20892-5055. E-mail: robertsa{at}dce41.nci.nih.gov
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