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D. Bhasin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 391–395
Table 1. Anti-proliferative activity of STA 21 and compounds 1–4 on prostate cancer cell lines DU145, PC3, LNCaP, and breast cancer cell line
MCF-7
Drug
DU145 IC50 (lM)
PC3 IC50 (lM)
LNCaP IC50 (lM)
MCF-7 IC50 (lM)
STA 21
12.2
16.2
31.5
>100
>100
18.7
13.4
32.4
>100
>100
Not tested
34.1
31.5
124
88.5
1
2
3
4
Not tested
Not tested
Not tested
>100
>100
Cells (2000 cells/well) were treated with varying concentrations of the compounds and cell associated protein was determined using MTS assay. The
IC50 values represent means of two experiments in triplicate. Values are the average of two separate experiments.
2. Levy, D. E.; Darnell, J. E., Jr. Nat. Rev. Mol. Cell. Biol.
2002, 3, 651.
3. Shuai, K.; Horvath, C. M.; Huang, L. H.; Qureshi, S. A.;
Cowburn, D.; Darnell, J. E., Jr. Cell 1994, 76, 821.
4. Sasse, J.; Hemmann, U.; Schwartz, C.; Schniertshauer, U.;
Heesel, B.; Landgraf, C.; Schneider-Mergener, J.; Hein-
rich, P. C.; Horn, F. Mol. Cell. Biol. 1997, 17, 4677.
5. Zhong, Z.; Wen, Z.; Darnell, J. E., Jr. Science 1994, 264, 95.
6. Darnell, J. E., Jr.; Kerr, I. M.; Stark, G. R. Science 1994,
264, 1415.
7. Grandis, J. R.; Drenning, S. D.; Chakraborty, A.; Zhou,
M. Y.; Zeng, Q.; Pitt, A. S.; Tweardy, D. J. J. Clin. Invest.
1998, 102, 1385.
8. Catlett-Falcone, R.; Landowski, T. H.; Oshiro, M. M.;
Turkson, J.; Levitzki, A.; Savino, R.; Ciliberto, G.;
Moscinski, L.; Fernandez-Luna, J. L.; Nunez, G.; Dalton,
W. S.; Jove, R. Immunity 1999, 10, 105.
9. Catlett-Falcone, R.; Dalton, W. S.; Jove, R. Curr. Opin.
Oncol. 1999, 11, 490.
10. Turkson, J.; Jove, R. Oncogene 2000, 19, 6613.
11. Bowman, T.; Garcia, R.; Turkson, J.; Jove, R. Oncogene
Figure 5. Predicted binding model of compound 2 to STAT3b. The
model was predicted by Autodock (v 4.0). Only the residues that form
hydrogen bonds with the compound are shown.
2000, 19, 2474.
12. Buettner, R.; Mora, L. B.; Jove, R. Clin. Cancer Res. 2002,
8, 945.
anti-proliferative activities against all three cell lines
(DU145, PC3, and LNCaP). Compound 2 had the 8-
OH group instead of the 5-OH on the anthracene moiety
13. Mora, L. B.; Buettner, R.; Seigne, J.; Diaz, J.; Ahmad, N.;
and could not form a hydrogen bond with Ile 634 at the
SH-2 domain. However, molecular docking revealed
that the 8-OH group of compound 2 was H-bonded to
Glu 594 at the SH2 domain (Fig. 5). This may explain
the anti-proliferative activities of the compound.
Garcia, R.; Bowman, T.; Falcone, R.; Fairclough, R.;
Cantor, A.; Muro-Cacho, C.; Livingston, S.; Karras, J.;
Pow-Sang, J.; Jove, R. Cancer Res. 2002, 62, 6659.
14. Barton, B. E.; Karras, J. G.; Murphy, T. F.; Barton, A.;
Huang, H. F. Mol. Cancer Ther. 2004, 3, 11.
15. Dhir, R.; Ni, Z.; Lou, W.; DeMiguel, F.; Grandis, J. R.;
Gao, A. C. Prostate 2002, 51, 241.
In conclusion, we have successfully modified our small
molecule STAT3 inhibitor STA 21 to generate a struc-
turally simpler molecule (compound 1). Molecular dock-
ing showed that compound 1 bound to the STAT3b
SH2 domain in a similar manner as STA 21. Compound
1 also exhibited the same anti-proliferative activities as
STA 21 against prostate cancer cell lines that express
constitutively active STAT3. Thus, compound 1 serves
as a lead compound for the design of more potent and
selective STAT3 inhibitors.
16. DeMiguel, F.; Lee, S. O.; Lou, W.; Xiao, X.; Pflug, B. R.;
Nelson, J. B.; Gao, A. C. Prostate 2002, 52, 123.
17. Lee, S. O.; Lou, W.; Qureshi, K. M.; Mehraein-Ghomi, F.;
Trump, D. L.; Gao, A. C. Prostate 2004, 60, 303.
18. Gao, L.; Zhang, L.; Hu, J.; Li, F.; Shao, Y.; Zhao, D.;
Kalvakolanu, D. V.; Kopecko, D. J.; Zhao, X.; Xu, D. Q.
Clin. Cancer Res. 2005, 11, 6333.
19. Nam, S.; Buettner, R.; Turkson, J.; Kim, D.; Cheng, J. Q.;
Muehlbeyer, S.; Hippe, F.; Vatter, S.; Merz, K. H.;
Eisenbrand, G.; Jove, R. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 5998.
20. Kotha, A.; Sekharam, M.; Cilenti, L.; Siddiquee, K.;
Khaled, A.; Zervos, A. S.; Carter, B.; Turkson, J.; Jove, R.
Mol. Cancer Ther. 2006, 5, 621.
Acknowledgments
21. Sun, J.; Blaskovich, M. A.; Jove, R.; Livingston, S. K.;
Coppola, D.; Sebti, S. M. Oncogene 2005, 24, 3236.
22. Yu, H.; Jove, R. Nat. Rev. Cancer 2004, 4, 97.
23. Kaptein, A.; Paillard, V.; Saunders, M. J. Biol. Chem.
1996, 271, 5961.
This research is partially supported by the James S.
McDonnell Foundation.
24. Leong, P. L.; Andrews, G. A.; Johnson, D. E.; Dyer, K.
F.; Xi, S.; Mai, J. C.; Robbins, P. D.; Gadiparthi, S.;
Burke, N. A.; Watkins, S. F.; Grandis, J. R. Proc. Natl.
Acad. Sci. U.S.A. 2003, 100, 4138.
References and notes
1. Horvath, C. M.; Darnell, J. E. Curr. Opin. Cell. Biol. 1997,
9, 233.