TGF-β Type I Receptor Inhibitor

　RepSox (1) is a cell permeable TGF-β type I receptor inhibitor. 1 shows inhibition properties on ALK5 as shown in Table 1 and less potent activity against 9 other related kinases, including p38 MAPK, JNK1, and GSK3 (IC₅₀ > 16 μM).¹⁾ 1 promotes reprogramming of human and mouse embryonic fibroblasts to induced pluripotent stem cells (iPSCs).^2,3) In addition, it was also reported that 1 induces human ESCs and iPSCs into glucagon-producing cells and insulin-producing cells, respectively.^4,5)

References

• 1) Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-β type I receptor inhibitors
• F. Gellibert, J. Woolven, M.-H. Fouchet, N. Mathews, H. Goodland, V. Lovegrove, A. Laroze, V.-L. Nguyen, S. Sautet, R. Wang, C. Janson, W. Smith, G. Krysa, V. Boullay, A.-C. de Gouville, S. Huet, D. Hartley, J. Med. Chem. 2004, 47, 4494.
• 2) A small-molecule inhibitor of Tgf-β signaling replaces Sox2 in reprogramming by inducing Nanog
• J. K. Ichida, J. Blanchard, K. Lam, E. Y. Son, J. E. Chung, D. Egli, K. M. Loh, A. C. Carter, F. P. Di Giorgio, K. Koszka, D. Huangfu, H. Akutsu, D. R. Liu, L. L. Rubin, K. Eggan, Cell Stem Cell 2009, 5, 491.
• 3) Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells.
• D. Subramanyam, S. Lamouille, R. L. Judson, J. Y. Liu, N. Bucay, R. Derynck, R. Blelloch, Nat. Biotechnol. 2011, 29, 443.
• 4) Small molecules induce efficient differentiation into insulin-producing cells from human induced pluripotent stem cells
• Y. Kunisada, N, Tsubooka-Yamazoe, M. Shoji, M. Hosoya, Stem Cell Res. 2012, 8, 274.
• 5) Production of functional glucagon-secreting α-cells from human embryonic stem cells
• A. Rezania, M. J. Riedel, R. D. Wideman, F. Karanu, Z. Ao, G. L. Warnock, T. J. Kieffer, Diabetes 2011, 60, 239.

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