ACS Medicinal Chemistry Letters
LETTER
15a, 20a, 24a, 25a, and 26a, were screened at a concentration of
10 μM, which revealed a significant number of potential kinase
targets for this inhibitor class (please see the Supporting In-
formation Ambit profiling data for details). Compound 20a has
slightly better potency than compound 15a, but 20a exhibits less
selectivity with the KINOMEscan selectivity score S10 of 0.31
(123/402) as compared to 15a with the S10 of 0.21. Similarly, as
compared to 20a, the thio urea 24a has better potency against
ALK but also possesses dramatically decreased selectivity with
the S10 of 0.62, which could be the reason for its cytotoxicity to
parental Ba/F3 cells. The 2-alkyloxy substituent on the aromatic
ring of 3-aniline side chain serves as the selectivity handle
evidenced by the S10 of 15a, 25a, and 26a, which are 0.21,
0.13, and 0.06, respectively. This is consistent with the finding
that the ortho methoxy group attached to the 2-aniline sub-
stituent in 1 offering its selectivity of ALK over other tested
kinases.11 For comparison, the 3,5-diamino-1,2,4-triazole urea
scaffold possesses overall improved selectivity when compared
’ ABBREVIATIONS
ALK, anaplastic lymphoma kinase; ALCL, anaplastic large
cell lymphoma; ATP, adenosine triphosphate; CDK1, cyclin-
dependent kinase 1; DLBCL, diffuse large B cell lymphoma;
EML4, echinoderm microtubule-associated protein-like 4; IMT,
inflammatory myofibroblastic tumors; InsR, insulin receptor
kinase; NSCLC, nonsmall cell lung cancer.
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’ ASSOCIATED CONTENT
S
Supporting Information. Procedures and characteriza-
b
tion data for all compounds, procedures for cellular assay, crystal
structures of 29a and 29b, and kinase selectivity profiling data for
1, 15a, 20a, 24a, 25a, and 26a. This material is available free of
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II; Zhang, J.; AhnY., Y.; ZhouW., W.; LondonW. B., W. B.; McGradyP.,
P.; XueL., L.; ZozulyaS., S.; GregorV. E., V. E.; WebbT. R., T. R.; GrayN.
S., N. S.; GillilandD, D. G.; DillerL., L.; Greulich, H.; Morris, S. W.;
Meyerson, M.; Look, A. T. Activating mutations in ALK provide a
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Sun, F.; Schultz, P. G.; Gray, N. S.; Warmuth, M. Identification of NVP-
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’ AUTHOR INFORMATION
Corresponding Author
*Tel: 1-617-582-8590. Fax: 1-617-582-8615. E-mail: Nathanael_
Author Contributions
^These authors contributed equally.
Funding Sources
This work was supported by an NCI Grant 1 R01 CA136851-
01A1 (N.S.G. and P.A.J.) and 1 R01 CA148688-01A1 (R.E.G.).
’ ACKNOWLEDGMENT
We thank Life Technologies Corporation, SelectScreen Ki-
nase Profiling Service, for performing the enzymatic biochemical
kinase profiling and Ambit Bioscience for performing KinomeS-
can profiling.
(13) Chen, Z.; Sasaki, T.; Tan, X.; Carretero, J.; Shimamura, T.; Li,
D.; Xu, C.; Wang, Y.; Aldelmant, G. O.; Capelletti, M.; Lee, H. J.; Rodig,
S. J.; Borgman, C. L.; Park, S. I.; Kim, H. R.; Padera, R. F., Jr.; Marto, J.;
Gray, N.; Kung, A. L.; Shapiro, G. I.; Janne, P. A.; Wong, K. K. Inhibition
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dx.doi.org/10.1021/ml200002a |ACS Med. Chem. Lett. 2011, 2, 379–384