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Table 3
References and notes
Kinase inhibition profile of 8h against selected kinases
1. (a) Druker, B. J.; Guilhot, F.; O’Brien, S. G.; Gathmann, I.; Kantarjian, H.;
Kinase
IC50 (nM)
Kinase
IC50 (nM)
Gattermann, N.; Deininger, M. W.; Silver, R. T.; Goldman, J. M.; Stone, R.
M.; Cervantes, F.; Hochhaus, A.; Powell, B. L.; Gabrilove, J. L.; Rousselot, P.;
Reiffers, J.; Cornelissen, J. J.; Hughes, T.; Agis, H.; Fischer, T.; Verhoef, G.;
Shepherd, J.; Saglio, G.; Gratwohl, A.; Nielson, J. L.; Radich, J. P.;
Simonsson, B.; Taylor, K.; Baccarani, M.; So, C.; Letvak, L.; Larson, R. A.
N. Engl. J. Med. 2006, 355, 2408; (b) Druker, B. J.; Tamura, S.; Buchdunger,
E.; Ohno, S.; Segal, G. M.; Fanning, S.; Zimmermann, J.; Lydon, N. B. Nat.
Med. 1996, 2, 561; (c) Capdeville, R.; Buchdunger, E.; Zimmermann, J.;
Matter, A. Nat. Rev. Drug Disc. 2002, 1, 493.
ABL
ABL(T315I)
BRAF
BRAF (V599E)
Aurora A
CDK2/cycline E
c-Kit
c-Met
EGFR
EGFR (L858R)
EGFR (L858R T790M)
EGFR (T790M)
EPHA2
0.2
0.4
20
26
>3000
6.4
>3000
>3000
736
231
>3000
>3000
0.6
FGFR3
FGFR4
VEGFR1
VEGFR2
VEGFR3
FMS
IR
JAK1
JAK2
JAK3
10.5
34
5.2
2.3
2.6
7.2
>3000
55.3
536
57.5
2.0
<0.15
1.3
2.6
2. O’Hare, T.; Eide, C. A.; Deininger, M. W. Blood 2007, 110, 2249.
3. (a) Weisberg, E.; Manley, P. W.; Breitenstein, W.; Brueggen, J.; Cowan-Jacob, S.
W.; Ray, A.; Huntly, B.; Fabbro, D.; Fendrich, G.; Hall-Meyers, E.; Kung, A. L.;
Mestan, J.; Daley, G. Q.; Callahan, L.; Catley, L.; Cavazza, C.; Mohammed, A.;
Neuberg, D.; Wright, R. D.; Gilliland, D. G.; Griffin, J. D. Cancer Cell 2005, 7, 129;
(b) Shah, N. P.; Tran, C.; Lee, F. Y.; Chen, P.; Norris, D.; Sawyers, C. L. Science
2004, 305, 399.
FLT3
LYN
PDGFR
a
EPHA3
1.2
PDGFRb
EPHA7
FGFR1
FGFR2
4.2
1.8
1.5
RET
Tie2/TEK
Src
0.2
2.2
4.0
4. (a) O’Hare, T.; Walters, D. K.; Stoffregen, E. P.; Jia, T.; Manley, P. W.; Mestan, J.;
Cowan-Jacob, S. W.; Lee, F. Y.; Heinrich, M. C.; Deininger, M. W. N.; Druker, B. J.
Cancer Res. 2005, 65, 4500; (b) Deguchi, Y.; Kimura, S.; Ashihara, E.; Niwa, T.;
Hodohara, K.; Fujiyama, Y.; Maekawa, T. Leuk. Res. 2008, 32, 980; (c) Redaelli, S.;
Piazza, R.; Rostagno, R.; Magistroni, V.; Perini, P.; Marega, M.; Gambacorti-
Passerini, C.; Boschelli, F. J. Clin. Oncol. 2009, 27, 469.
5. Huang, W.-S.; Zhu, X.; Wang, Y.; Azam, M.; Wen, D.; Sundaramoorthi, R.;
Thomas, R. M.; Liu, S.; Banda, G.; Lentini, S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.;
Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Daley, G. Q.;
Iuliucci, J.; Dalgarno, D. C.; Clackson, T.; Sawyer, T. K.; Shakespeare, W. C. J. Med.
Chem. 2009, 52, 4743.
6. O’Hare, T.; Shakespeare, W. C.; Zhu, X.; Eide, C. A.; Rivera, V. M.; Wang, F.;
Adrian, L. T.; Zhou, T.; Huang, W.-S.; Xu, Q.; Metcalf, C. A.; Tyner, J. W.; Loriaux,
M. M.; Corbin, A. S.; Wardwell, S.; Ning, Y.; Keats, J. A.; Wang, Y.;
Sundaramoorthi, R.; Thomas, M.; Zou, D.; Snodgrass, J.; Commodore, L.;
Sawyer, T. K.; Dalgarno, D. C.; Deininger, M. W. N.; Druker, B. J.; Clackson, T.
Cancer Cell 2009, 16, 401.
7. Huang, W.-S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y.; Zou, D. R.; Thomas,
M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.; Qi, J.; Chen, I.; Banda, G.; Lentini,
S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.;
Broudy, M. I.; Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N.;
Mohemmad, Q.; Luliucci, J.; Rivera, V. M.; Dalgarno, D. C.; Sawyer, T. K.;
Clackson, T.; Shakespeare, W. C. J. Med. Chem. 2010, 53, 4701.
8. Shakespeare, W. C.; Huang, W.-S.; Dalgarno, D. C.; Zhu, X.; Thomas, R. M.;
Wang, Y.; Qi, J.; Sundaramoorthi, R.; Zou, D.; Metcalf, C.A.; Sawyer, T. K.;
Romero, J.C. PCT Int. Appl. WO2007133562.
In summary, we describe a strategy to design an orthogonal ser-
ies of BCR–ABL inhihitors bearing monocyclic hinge-binding tem-
plates, evolved from our clinical candidate and pan-BCR–ABL
inhibitor, ponatinib. Lead compounds from this series potently in-
hibit ABL kinase activity and proliferation of Ba/F3 cells expressing
both native BCR–ABL and BCR–ABLT315I with low nM IC50s. Multi-
ple compounds in the series exhibited favorable rat and mouse
pharmacokinetic profiles, and 8h exhibited efficacy similar to
ponatinib in an aggressive mouse model of CML driven by the
T315I mutant of BCR–ABL. The additional hinge region H-bond ap-
pears to compensate for the decreased hydrophobic interactions of
the monocycle relative to the 6,5-fused bicycle in ponatinib in
terms of in vitro and in vivo activity, and has almost no effect on
kinase selectivity. Monocyclic derivatives such as 8h may be useful
for targeting multiple kinases, including those bearing gatekeeper
mutations, and therefore could prove useful in the treatment of
tumor types where these kinases play a key role.
9. Deng, X.; Lim, S. M.; Zhang, J.; Gray, N. S. Bioorg. Med. Chem. Lett. 2010,
20, 4196.
10. Zhou, T.; Commodore, L.; Huang, W.-S.; Wang, Y.; Thomas, M.; Keats, J.; Xu, Q.;
Rivera, V. M.; Shakespeare, W. C.; Clackson, T.; Dalgarno, D. C.; Zhu, X. Chem.
Biol. Drug Des. 2011, 77, 1.
Acknowledgments
11. Chittiboyina, A. G.; Raji, R.; Blake, W. E.; Avery, M. A. Tetrahedron Lett. 2004, 45,
1869.
The authors thank Narayana Narasimhan and Manfred Weigele
from ARIAD for useful discussions.