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Figure 4. Comparison of the prospective predicted binding geometry
of the difluoroanalog of 2i (carbons in yellow) and the observed crystal
structures of the original lead compound 1 (carbons in green) and the
2i compound (carbons in light blue) bound to CDK2.
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Of particular interest is the observed specificity of this
class of compounds for CDKs over other kinases.Com-
pound 2i has shown no detectable effect when tested
against a representative set of other serine/threonine ki-
nases such as GSK3b, CAMKII, PKA, PKC-a,b,e,c.
This compound inhibits proliferation in HCT 116 cells
in tissue culture as determined by an MTT assay
(IC50 = 5. 5lM).
8. (a) Misra, R. N.; Xiao, H.-y.; Williams, D. K.; Kim, K. S.;
Lu, S.; Keller, K. A.; Mulheron, J. G.; Batorsky, R.;
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9. (a) Hamdouchi, C.; Keyser, H.; Collins, E.; Jaramillo, C.;
de Diego, E.; Spencer, C.; Dempsey, J.; Anderson, B.;
Leggett, T.; Stamm, N.; Schultz, R.; Watkins, S.; Cocke,
K.; Lemke, S.; Burke, T.; Beckmann, R.; Dixon, J.;
Gurganus, T.; Rankl, N.; Houck, K. A.; Zhang, F.; Vieth,
M.; Espinosa, J.; Timm, D.; Campbell, R.; Patel, B.;
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H.; Watkins, S.; Spencer, C.; Dempsey, J.; Anderson, B.;
Leggett, T.; Schultz, R.; Watkins, S.; Lemke, S.; Burke, T.;
Beckmann, R.; Dixon, J.; Gurganus, T.; Rankl, N.;
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In conclusion, we have identified a highly selective struc-
tural class of cyclin dependent kinase inhibitors by modif-
ying aminoimidazo[1,2-a]pyridines scaffold.Structural-
based design approach was successfully used to investi-
gate and design new compounds that were able to form
a new interaction with an identified residue of the pro-
tein, Lys89.This new interaction eliminated the need
for internal hydrogen bonds.These compounds were
found to compete with ATP for binding to a catalytic
subunit of the protein.Initial structure features required
for activity were defined.Further studies, including in
vivo activities and additional structure-activity relation-
ships are underway.
Acknowledgements
We are grateful to Dr.Chuan Shih and the Lilly Kinase
Platform for the advice and helpful discussions.
10. (a) Hamdouchi, C.; Sanchez, C.; Ezquerra, J. Synthesis
1998, 867; (b) Hamdouchi, C.; de Blas, J.; del Prado, M.;
Gruber, J.; Heinz, B. A.; Vance, L. J. Med. Chem. 1999,
42, 50.
11.Final compounds were characterized by 400/500 MHz 1H
NMR, HRMS, and LC/MS (97%).
References and notes
12.The crystal structure of compound 2i bound to monomeric
human CDK2 has been deposited in the Protein Data
Bank with deposition code 1YKR together with structure
factors and detailed experimental condition.
13. Wu, G.; Robertson, D. H.; Brooks, C. L., III; Vieth, M. J.
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