6192 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 20
Smith et al.
an opportunity for kinase selectivity that was exploited suc-
cessfully with an aminoisoquinoline core. Additional selectiv-
ity was exploited through subtle differences in the extended
hydrophobic pockets of the kinases, and potency was opti-
mized through changes in the hinge-binding region through
the introduction of a purine moiety. This led to the identifica-
tion of 1 as a potent, highly selective inhibitor of Raf6 that
demonstrates potent antitumor activity in an in vivo melano-
ma model driven by the mutant B-Raf pathway. Although 1
was apparently well tolerated, this group will present else-
where data that suggest potent Raf inhibitors can lead to
compensatory activation of the MAPK pathway with unde-
sirable functional consequences observed in normal tissues
and certain other non-B-Raf mutant tumor models in vivo.
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Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird,
A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman,
J. G.; Wilson, D. M. The identification of potent and selective imidazole-
based inhibitors of B-Raf kinase. Bioorg. Med. Chem. Lett. 2006, 16,
378–381. (c) Tang, J.; Hamajima, T.; Nakano, M.; Sato, H.; Dickerson, S.
H.; Lackey, K. E. Knowledge-based design of 7-azaindoles as selective
B-Raf inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 4610–4614. (d)
Hoeflich, K. P.; Herter, S.; Tien, J.; Wong, L.; Berry, L.; Chan, J.; O'Brien,
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B. K.; Bellon, S.; Bready, J.; Caenepeel, S.; Cee, V. J.; Chaffee, S. C.;
Coxon, A.; Emery, M.; Fretland, J.; Gallant, P.; Gu, Y.; Hoffman,
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of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2
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B.; Hodous, B. L.; Hsieh, F.; Huang, X.; Kim, J. L.; Lee, J. H.;
Martin, M. W.; Masse, C. E.; McGowan, D. C.; Metz, D.; Mohn, D.;
Morgenstern, K. A.; Oliveira-dos-Santos, A.; Patel, V. F.; Powers, D.;
Rose, P. E.; Schneider, S.; Tomlinson, S. A.; Tudor, Y.-Y.; Turci, S. M.;
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Acknowledgment. We thank our colleagues Stephanie
Geuns-Meyer for the synthesis of 2, Rob Wahl for performing
the high-throughput screen that identified 2, Christina Boucher,
Christie Binder, and Shaun Flynn for running kinase counter-
screening assays, Xiao Ding, Michelle Kelly, and Tom Menges
for performing pharmacokinetic studies, and Andrew Tasker,
Rick Kendall, and Terri Burgess for helpful discussions.
Note Added after ASAP Publication. There was an error in
the Abbreviations in the version of this paper published on
September 18, 2009. The revised version was published on
September 22, 2009.
(6) No selectivity was observed for these compounds between V600EB-
Raf and wild type B-Raf or C-Raf in enzyme assays in vitro.
(7) Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.;
Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.;
Regan, J. Inhibition of p38 MAP kinase by utilizing a novel
allosteric binding site. Nat. Struct. Biol. 2002, 9, 268–272.
Supporting Information Available: Synthesis details for com-
pounds described herein, analytical data, X-ray crystallographic
data, kinase counterscreening data for 1, and PD-efficacy data
for the compounds shown in Figure 4. This material is available
(8) Cancer Genome Project. Wan, P. T. C.; Garnett, M. J.; Roe, S. M.;
Lee, S.; Niculescu-Duvaz, D.; Good, V. M.; Jones, C. M.; Marshall,
C. J.; Springer, C. J.; Barford, D.; Marais, R. Mechanism of
activation of the RAF-ERK signaling pathway by oncogenic
mutations of B-RAF. Cell 2004, 116, 855–867.
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(4) Plexxikon filed an IND in 2006 for PLX-4032. Exelixis filed an
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(12) The cocrystal structure of B-Raf with 1 has been deposited in the
Protein Data Bank with accession code 3IDP.
(13) Human A375 cells were selected in vivo by passaging twice
subcutaneously in CD1 nu/nu mice to optimize for tumor take
and growth. This cell line was designated A375 SQ2.
(14) Compound was dosed QD in a randomized, blinded experiment for
14 days starting 17 days postimplantation.