4584
X. Deng et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4579–4584
EC50 of 120 nM on parental Ba/F3 cells suggesting that this com-
pound engaged additional targets. We next investigated modifica-
tions to the 3-amino group of the 1H-indazole, which is predicted
to interact with the hinge region of the kinase. Acetyl, free amino
and methyl analogs (17, 18 and 22) exhibited EC50s of single-digit
and reproduced with permission from Cell Signaling Technology,
Supplementary data
nanomolar potency against FLT3 and PDGFR
activity on Kit-T670I.
a-T674M, but lost
Supplementary data associated with this article can be found, in
05.107. These data include MOL files and InChiKeys of the most
important compounds described in this article.
To better understand the structure and activity relationship of
this amino-indazole scaffold, we performed a modeling study by
comparing the binding mode of compound 4 with HG-7-85-01 in
the co-crystal structure of c-Src (PDB ID: 4agw)7 and with
AP24534 in a co-crystal structure with T315I Abl (PDB ID: 3ik3)4
(Fig. 3).17 Superimposing the bound conformation of 4 and HG-7-
85-01, 4 is predicted to bind to Src in the ‘DFG-out’ inactive confor-
mation and form four hydrogen bonding interactions (Fig. 3a). One
hydrogen bond is predicted between the hinge region backbone
carbonyl of E339 and the indazole NH. A pair of hydrogen bonds
are predicted between the benzamide carbonyl and the backbone
NH of D404 of the ‘DFG-motif’ and the benzamide NH and side
References and notes
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compounds such as 4 and 22 are not general cytotoxic agents
and exhibit more than 1000-fold selectivity for FLT3 and Kit-
T670I dependent cellular growth. Further medicinal chemistry ef-
forts are in progress to develop analogs from this compound series
whose multitargeted inhibition profile is tailored for optimal activ-
ity against particular cancer genotypes.
15. The image was generated by using the web-based TREEspotTM software
(Ambit Biosciences, now part of DiscoveRx Corp.).
Acknowledgments
16. Melnick, J. S.; Janes, J.; Kim, S.; Chang, J. Y.; Sipes, D. G.; Gunderson, D.; Jarnes,
L.; Matzen, J. T.; Garcia, M. E.; Hood, T. L.; Beigi, R.; Xia, G.; Harig, R. A.;
Asatryan, H.; Yan, S. F.; Zhou, Y.; Gu, X. J.; Saadat, A.; Zhou, V.; King, F. J.; Shaw,
C. M.; Su, A. I.; Downs, R.; Gray, N. S.; Schultz, P. G.; Warmuth, M.; Caldwell, J. S.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3153.
This work was supported by the NIH Grant number CA130876-
02. We thank Ambit Biosciences for technical support in the com-
pound KINOMEscan profiling and Maria Nicolais for helping with
Cell-Titer Glo experiments. The kinase dendrogram was adapted
17. Glide version 3.5 program was used for the docking study.