G. T. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6067–6071
6071
Figure 2. Heat map showing the inhibitory activity of compound 11 against 80 kinases. Pink: IC50 <10 nM; Red: IC50 10–100 nM; Yellow: IC50 100–1000 nM; Gray: IC50
>1000 nM.
6. Guix, M.; Faber, A. C.; Wang, S. E.; Olivares, M. G.; Song, Y.; Qu, S.; Rinehart, C.
The kinase selectivity of compound 11 was assessed against a
panel of 80 kinases and the results are shown in a heat map
R.; Seidel, B.; Yee, D.; Arteaga, C. L.; Engelman, J. A. J. Clin. Invest. 2008, 118,
2609.
(Fig. 2). Besides the intended receptor tyrosine kinases (IGF1R,
IR, EGFR, ErbB2), compound 11 also potently inhibits several of
the Src family of non-receptor tyrosine kinases including Fyn,
Lyn, and Lck. This was not surprising in consideration of litera-
ture reports on related compounds as Src family inhibitors.19
Unexpectedly, the compound also inhibits the Aurora family of
serine–threonine kinases, being particularly potent against Aur-
ora B.
In summary, we have identified a series of substituted 4-amino-
1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR,
and ErbB2 receptor kinases. Many analogs showed potent and bal-
anced activity against all three target enzymes, as exemplified by
the leading compound 11 (IGF1R IC50 of 12 nM, EGFR (L858R)
IC50 of 31 nM, and ErbB2 IC50 of 11 nM). In cellular functional as-
says, these compounds potently inhibit the phosphorylation of
7. Haluska, P.; Carboni, J. M.; TenEyck, C.; Attar, R. M.; Hou, X.; Yu, C.; Sagar, M.;
Wong, T. W.; Gottardis, M. M.; Erlichman, C. Mol. Cancer Ther. 2008, 7, 2589.
8. Wilsbacher, J. L.; Zhang, Q.; Tucker, L. A.; Hubbard, R. D.; Sheppard, G. S.;
Bamaung, N. Y.; Fidanze, S. D.; Wang, G. T.; Hu, X.; Davidsen, S. K.; Bell, R. L.;
Wang, J. J. Biol. Chem. 2008, 283, 23712.
9. Charkraborty, A. K.; Liang, K.; DiGiovanna, M. P. Cancer Res. 2008, 68, 1538.
10. Lu, D.; Zhang, H.; Koo, H.; Tonra, J.; Balderes, P.; Prewett, M.; Corcoran, E.;
Mangalampalli, V.; Bassi, R.; Anselma, D.; Patel, D.; Kang, X.; Ludwig, D. L.;
Hicklin, D. J.; Witte, L.; Zhu, Z. J. Biol. Chem. 2005, 280, 19665.
11. Goetsch, L.; Gonzalez, A.; Leger, O.; Beck, A.; Pauwels, P. J.; Haeuw, J. F.; Corvaia,
N. Intl. J. Cancer 2005, 113, 316.
12. Hubbard, R. D.; Bamaung, N. Y.; Fidanze, S. D.; Erickson, S. A.; Palazzo, F.;
Wilsbacher, J. L.; Zhang, Q.; Tucker, L. A.; Hu, X.; Kovar, P.; Osterling, D. J.;
Johnson, E. F.; Bouska, J.; Wang, J.; Davidsen, S. K.; Bell, R. L.; Sheppard, G. S.
Bioorg. Med. Chem. Lett. 2009, 19, 1718.
13. Hubbard, R. D.; Bamaung, N. Y.; Palazzo, F.; Zhang, Q.; Kovar, P.; Osterling, D. J.;
Hu, X.; Wilsbacher, J. L.; Johnson, E. F.; Bouska, J.; Wang, J.; Bell, R. L.; Davidsen,
S. K.; Sheppard, G. S. Bioorg. Med. Chem. Lett. 2007, 17, 5406.
14. (a) Hirst, G. C.; Calderwood, D.; Wishart, N.; Rafferty, P.; Ritter, K.; Arnold, L. D.;
Friedman, M. M. WO 01/19829.; (b) Borhan, D.; Calderwood, D.; Dixon, R. W.;
Hirst, G. C.; Hrnciar, P.; Loew, A.; Leung, A.; Ritter, K. WO 03/020880.
15. The kinase inhibitory activities of the test compounds were measured using a
homogeneous time-resolved fluorescence assay, as described in Ref. 12.
16. Lackey, K. Curr. Top. Med. Chem. 2006, 6, 435.
IGF1R and ErbB2, but not EGFR (EC50 >1 lM). Compound 11 also
showed activity in an in vivo pharmacodynamic assay of IGF1R
inhibition.
17. Ji, Q.; Mulvihill, M. J.; Rosenfeld-Franklin, M.; Cooke, A.; Feng, L.; Mak, G.;
O’Connor, M.; Yao, Y.; Pirritt, C.; Buck, E.; Eyzaguirre, A.; Arnold, L. D.; Gibson,
N. W.; Pachter, J. A. Mol. Cancer Ther. 2007, 6, 2158.
18. Garcia-Echeverria, C.; Pearson, M. A.; Marti, A.; Meyer, T.; Mestan, J.;
Zimmermann, J.; Gao, J.; Brueggen, J.; Capraro, H.-G.; Cozens, R.; Evans, D. B.;
Fabbro, D.; Furet, P.; Porta, D. G.; Liebetanz, J.; Martiny-Baron, G.; Reutz, S.;
Hofmann, F. Cancer Cell 2004, 5, 231.
19. (a) Burchat, A.; Borhani, D. W.; Calderwood, D. J.; Hirst, G. C.; Li, B.; Stachlewitz,
R. F. Bioorg. Med. Chem. Lett. 2006, 16, 118; (b) Bohani, D. W.; Calderwood, D. J.;
Friedman, M. M.; Hirst, G. C.; Li, B.; Leung, K. W.; McRae, B.; Ratnofsky, S.;
Ritter, K.; Waegell, W. Bioorg. Med. Chem. Lett. 2004, 14, 2613.
References and notes
1. (a) Pollak, M. Nat. Rev. Cancer 2008, 8, 915; (b) Sachdev, D.; Yee, D. Mol. Cancer
Ther. 2007, 6, 1.
2. Hynes, N.; Lane, H. Nat. Rev. Cancer 2005, 5, 341.
3. Li, R.; Pourpak, A.; Morris, S. W. J. Med. Chem. 2009, 52, 4981.
4. Jones, H. E.; Goddard, L.; Gee, J. M. W.; Hiscox, S.; Rubini, M.; Barrow, D.;
Knowlden, J. M.; Williams, S.; Walkeling, A. E.; Nicholson, R. I. Endocr. Relat.
Cancer 2004, 11, 793.
5. Nahta, R.; Yuan, L. Y.; Du, Y.; Esteva, F. J. Mol. Cancer Ther. 2007, 6, 667.