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B. Lippa et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3359–3363
Table 2. Akt kinase and cell potency of spiroindolines 13a– j
R2
N
R1
R3
N
N
N
N
13
H
a
Akt1 kinase IC50 (nM)
a
Compound
R1
R2
R3
Akt cell IC50 (nM)
96
51 33
13a
13b
13c
13d
13e
13f
13g
13h
13i
H
Cl
F
H
H
5.3 0.9
4.8 1.2
3.1 1.9
9
H
H
H
H
75
6
H
F
Me
COMe
SO2Me
H
H
12.7 11.0
2790 318
3190 346
5.8 4.9
136
NT
NT
3
H
F
H
H
H
H
H
Cl
Me
Bn
64 49
122 19
NT
H
4.8 3.9
1330 572
2.4 0.6
H
13j
H
CN
50 19
a Values are means of at least two experiments; NT, not tested.
7. Carpten, J. D.; Faber, A. L.; Horn, C.; Donoho, G. P.;
Briggs, S. L.; Robbins, C. M.; Hostetter, G.; Boguslawski,
S.; Moses, T. Y.; Savage1, S.; Uhlik, M.; Lin, A.; Du, J.;
Qian, Y.-W.; Zeckner, D. J.; Tucker-Kellogg, G.; Touch-
man, J.; Patel, K.; Mousses, S.; Bittner, M.; Schevitz, R.;
Lai, M.-H. T.; Blanchard, K. L.; Thomas, J. E. Nature
2007, 448, 439.
8. Pedrero, J. M. G.; Carracedo, D. G.; Pinto, C. M.;
Zapatero, A. H.; Rodrigo, J. P.; Nieto, C. S.; Gonzalez,
M. V. Int. J. Cancer 2005, 114, 242.
9. Li, Q. Expert Opin. Ther. Patents 2007, 17, 1077.
10. Lindsley, C. W.; Barnett, S. F.; Yaroschak, M.; Bilodeau,
M. T.; Layton, M. E. Curr. Topics Med. Chem. 2007, 7,
1349.
11. Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R.
G.; Barnett, S. F.; Defeo-Jones, D.; Jones, R. E.;
Hartman, G. D.; Huff, J. R.; Huberb, H. E.; Duggan,
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resulted in tumor growth inhibition of 68% versus con-
trol, with plasma Cmax, Cave and total daily AUC con-
centrations of 705 ng/mL, 402 ng/mL, and 3216 ng h/
mL, respectively.
In conclusion, the use of structure based drug design
aided in the optimization of a high throughput screening
hit, resulting in the design of several new series and a
ꢀ100-fold increase in Akt1 inhibition. Compound 13j
was further shown to inhibit Akt in cells, and to slow
the growth of tumors in vivo. Kinase selectivity remains
a key concern. Further results in optimizing kinase selec-
tivity, Akt potency, and drug-like properties will be pub-
lished in due course.
Acknowledgments
12. Kozikowski, A. P.; Sun, H.; Brognard, J.; Dennis, P. A.
J. Am. Chem. Soc. 2003, 125, 1144.
Michael Luzzio, Kevin Freeman-Cook, Chiliu Chen,
Christopher Autry, Catherine Hulford, Kendra Nelson,
Gary Martinelli, Donn G. Wishka, Matthew Marx,
Yong Lu, Martin Wythes, Chakrapani Subramanyam,
William Hungerford, Jinshan Chen, Shang-Poa Chang,
Joel Arcari, Tricia Kwan, Carl Thompson, and Aaron
Kanter provided additional chemistry support. Addi-
tional biology support was received from Kevin Cole-
man, Kristina Rafidi, Kou Kou, Jing Lin, Erik
Soderstrom, and Lili Yao.
13. Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods,
K. W.; Song, X.; Li, T.; Diebold, R. B.; Luo, Y.; Liu, X.;
Guan, R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.;
Olsen, A.; Marsh, K. C.; Stoll, V. S.; Mamo, M.;
Polakowski, J.; Campbell, T. J.; Martin, R. L.; Gintant,
G. A.; Penning, T. D.; Li, Q.; Rosenberg, S. H.; Giranda,
V. L. J. Med. Chem. 2007, 50, 2990.
14. Luo, Y.; Shoemaker, A. R.; Liu, X.; Woods, K. W.;
Thomas, S. A.; De Jong, R.; Han, E. K.; Li, T.; Stoll,
V. S.; Powlas, J. A.; Oleksijew, A.; Mitten, M. J.; Shi,
Y.; Guan, R.; McGonigal, T. P.; Klinghofer, V.;
Johnson, E. F.; Leverson, J. D.; Bouska, J. J.; Mamo,
M.; Smith, R. A.; Gramling-Evans, E. E.; Zinker, B.
A.; Mika, A. K.; Nguyen, P. T.; Oltersdorf, T.;
Rosenberg, S. H.; Li, Q.; Giranda, V. L. Mol. Cancer
Ther. 2005, 4, 977.
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D. T.; Zhou, Y.; Del Rosario, M.; Kaufman, S.; Ma, S.;
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Chem. Lett. 2006, 16, 4163.
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