The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta.
Transforming growth factor (TGF)-beta signaling facilitates tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for the treatment of patients with such cancer. In this study, we synthesized and characterized a small molecule inhibitor, A-83-01, which is structurally similar to previously reported ALK-5 inhibitors developed by Sawyer et al. (2003) and blocks signaling of type I serine/threonine kinase receptors for cytokines of the TGF-beta superfamily (known as activin receptor-like kinases; ALKs). Using a TGF-beta-responsive reporter construct in mammalian cells, we found that A-83-01 inhibited the transcriptional activity induced by TGF-beta type I receptor ALK-5 and that by activin type IB receptor ALK-4 and nodal type I receptor ALK-7, the kinase domains of which are structurally highly related to those of ALK-5. A-83-01 was found to be more potent in the inhibition of ALK5 than a previously described ALK-5 inhibitor, SB-431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF-beta. In contrast, A-83-01 had little or no effect on bone morphogenetic protein type I receptors, p38 mitogen-activated protein kinase, or extracellular regulated kinase. Consistent with these findings, A-83-01 inhibited the epithelial-to-mesenchymal transition induced by TGF-beta, suggesting that A-83-01 and related molecules may be useful for preventing the progression of advanced cancers.
Tojo
Masayoshi
M
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Ariake, Koto-ku, Tokyo.
Hamashima
Yoshio
Y
Hanyu
Aki
A
Kajimoto
Tetsuya
T
Saitoh
Masao
M
Miyazono
Kohei
K
Node
Manabu
M
Imamura
Takeshi
T
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D006801:Humans; D008168:Lung / Q000166:cytology; D008907:Mink; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism / Q000502:physiology; D013859:Thiocarbamates / Q000494:pharmacology*; D013882:Thiosemicarbazones; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
C507011:A-83-01; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D013859:Thiocarbamates; D013882:Thiosemicarbazones; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human