Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7 1601
Groups of 3-Quinolinecarbonitriles on the Inhibition of Src
Kinase Activity. Bioorg. Med. Chem. Lett. 2003, 13, 3797-3800.
(18) Ziegler, C. B., J r.; Curran, W. V.; Kuck, N. A.; Harris, S. M.;
Lin, Y. I. Synthesis and Antibacterial Activity of some 7-Sub-
stituted 1-Ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic
Acids: Ethers, Secondary Amines and Sulfides as C7 Substit-
uents. J . Heterocycl. Chem. 1989, 26, 1141-1145.
(19) Nishimura, Y.; Minamida, A.; Matsumoto, J . A Intramolecular
Cyclization of 7-Substituted 6-Fluoro-1,8-naphthyridine and
-quinoline Derivatives. J . Heterocycl. Chem. 1988, 25, 479-
485.
(20) Hennequin, L. F.; Thomas, A. P.; J ohnstone, C.; Stokes, E. S.
E.; Ple, P. A. Lohmann, J .-J . M.; Ogilvie, D. J .; Dukes, M.;
Wedge, S. R.; Curwen, J . O.; Kendrew, J .; Lambert-van der
Brempt, C. Design and Structure-Activity Relationship of a New
Class of Potent VEGF Receptor Tyrosine Kinase Inhibitors. J .
Med. Chem. 1999, 42, 5369-5389.
(21) Smaill, J . B.; Rewcastle, G. W.; Bridges, A. J .; Zhou, H.;
Showalter, H. D. H.; Fry, D. W.; Nelson, J . M.; Sherwood, V.;
Elliott, W. L.; Vincent, P. W.; DeJ ohn, D. E.; Loo, J . A.; Greis,
K. D.; Chan, O. H.; Reyner, E. L.; Lipka, E.; Denny, W. A.
Tyrosine Kinase Inhibitors. 17. Irreversible Inhibitors of the
Epidermal Growth Factor Receptor: 4-(Phenylamino)quinazo-
line- and 4-(Phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides
Bearing Additional Solubilizing Functions. J . Med. Chem. 2000,
43, 1380-1397.
(22) The enzyme data reported here is from a LANCE format assay
that differs from the ELISA assay used in our earlier publica-
tions (refs 16, 17). Full details for this and the Abl enzyme assay
can be found in the Supporting Information.
(23) Gorre, M. E.; Mohammed, M.; Ellwood, K.; Hsu, N.; Paquette,
R. R.; Rao, P. N.; Sawyers, C. L. Clinical Resistance to STI-571
Cancer Therapy Caused by BCR-ABL Gene Mutation or Am-
plification. Science 2001, 293, 876-880.
(24) Corbin, A. S.; Buchdunger, E.; Pascal, F.; Druker, B. J . Analysis
of the Structural Basis of Specificity of Inhibition of the Abl
Kinase by STI571. J . Biol. Chem. 2002, 277, 32214-32219.
(25) Nimmanapalli, R.; Bhalla, K. Mechanisms of Resistance to
Imatinib Mesylate in Bcr-Abl-Positive Leukemias. Curr. Opin.
Oncolol. 2002, 14, 616-620.
(26) Shannon, K. M. Resistance in the Land of Molecular Cancer
Therapeutics. Cancer Cell 2002, 2, 99-102.
(27) La Rosee, P.; Corbin, A. S.; Stoffregen, E. P.; Deininger, M. W.;
Druker, B. J . Activity of the Bcr-Abl Kinase Inhibitor PD180970
Against Clinically Relevant Bcr-Abl Isoforms that Cause Resis-
tance to Imatinib Mesylate (Gleevec, STI571). Cancer Res. 2002,
62, 7149-7153.
(28) Huron, D. R.; Gorre, M. E.; Kraker, A. J .; Sawyers, C. L.; Rosen,
N.; Moasser, M. M. A Novel Pyridopyrimidine Inhibitor of Abl
Kinase Is a Picomolar Inhibitor of Bcr-abl-Driven K562 Cells
and is Effective Against STI571-resistant Bcr-abl Mutants. Clin.
Cancer Res. 2003, 9, 1267-1273.
(29) Von-Bubanoff, N.; Veach, D. R.; Miller, W. T.; Li, W.; Sanger,
J .; Peschel, C.; Bornmann, W. G.; Clarkson, B.; Duyster, J .
Inhibition of Wild-Type and Mutant Bcr-Abl by Pyrido-Pyrimi-
dine Small Molecule Kinase Inhibitors. Cancer Res. 2003, 63,
6395-6404.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails, H NMR, HRMS, and analytical data for all compounds
and the enzyme assay protocols. This material is available free
1
Refer en ces
(1) Frame, M. C. Src in Cancer: Deregulation and Consequences
for Cell Behavior. Biochim. Biophys. Acta 2002, 1602, 114-130.
(2) Irby, R. B.; Yeatman, T. J . Role of Src Expression and Activation
in Human Cancer. Oncogene 2000, 19, 5636-5642.
(3) Martin, G. S. The Hunting of the Src. Nature Rev. Mol. Cell Biol.
2001, 2, 467-475.
(4) Summy, J . M.; Gallick, G. E. Src Family Kinases in Tumor
Progression and Metastasis. Cancer Metastasis Rev. 2003, 22,
337-358.
(5) Susa, M.; Missbach, M.; Green, J . Src Inhibitors: Drugs for the
Treatment of Osteoporosis, Cancer or Both? Trends Pharmacol.
Sci. 2000, 21, 489-495.
(6) Courtneidge, S. A. Role of Src in Signal Transduction Pathways.
Biochem. Soc. Trans. 2002, 30, 11-17.
(7) Golas, J . M.; Arndt, K.; Etienne, C.; Lucas, J .; Nardin, D.;
Gibbons, J .; Frost, P.; Ye, F.; Boschelli, D. H.; Boschelli, F. SKI-
606, a 4-Anilino-3-quinolinecarbonitrile Dual Inhibitor of Src and
Abl Kinases, is a Potent Antiproliferative Agent against Chronic
Myelogenous Leukemia Cells in Culture and Causes Regression
of K562 Xenografts in Nude Mice. Cancer Res. 2003, 63, 375-
381.
(8) Capdeville, R.; Buchdunger, E.; Zimmermann, J .; Matter, A.
Glivec (STI571, Imatinib), a Rationally Developed, Targeted
Anticancer Drug. Nature Rev. Drug Dis. 2002, 1, 493-502.
(9) Druker, B. J .; Lydon, N. B. Lessons Learned from the Develop-
ment of an Abl Tyrosine Kinase Inhibitor for Chronic Myelog-
enous Leukemia. J . Clin. Invest. 2000, 105, 3-7.
(10) Dorsey, J . F.; J ove, R.; Kraker, A. J .; Wu, J . The Pyrido[2,3-d]-
pyrimidine Derivative PD180970 Inhibits p210Bcr-Abl Tyrosine
Kinase and Induces Apoptosis of K562 Leukemic Cells. Cancer
Res. 2000, 60, 3127-3131.
(11) Wisniewski, D.; Lambek, C. L.; Liu, C.; Strife, A.; Veach, D. R.;
Nagar, B.; Young, M. A.; Schindler, T.; Bornmann, W. G.;
Bertino, J . R.; Kuriyan, J .; Clarkson, B. Characterization of
Potent Inhibitors of the Bcr-Abl and the c-Kit Receptor Tyrosine
Kinases. Cancer Res. 2002, 62, 4244-4255.
(12) Nimmanapalli, R.; O’Bryan, E.; Huang, M.; Bali, P.; Burnette,
P. K.; Loughran, T.; Tepperberg, J .; J ove, R.; Bhalla, K. Molec-
ular Characterization and Sensitivity of STI-571 (Imatinib
Mesylate, Gleevec)-Resistant, bcr-abl-Positive, Human Acute
Leukemia Cells to SRC Kinase Inhibitor PD180970 and 17-
Allylamino-17-demethoxygeldanamycin. Cancer Res. 2002, 62,
5761-5769.
(13) Warmuth, M.; Simon, N.; Mitina, O.; Mathes, R.; Fabbro, D.;
Manley, P. W.; Buchdunger, E.; Forster, K.; Moarefi, I.; Hallek,
M. Dual-specific Src and Abl Kinase Inhibitors, PP1 and
CGP76030, Inhibit Growth and Survival of Cells Expressing
Imatinib Mesylate-Resistant Bcr-Abl Kinases. Blood 2003, 101,
664-672.
(14) Metcalf, C., III; Wang, Y.; Shakespeare, W.; Sundaramoorthi,
R.; Keenan, T.; Dalgarno, D.; Bohacek, R.; Burns, K.; Roses, J .;
van Schravendijk, M. R.; Ram, M.; Keats, J .; Liou, S.; Adams,
S.; Snodgrass, J .; Rivera, V.; Weigle, M.; Iuliucci, J .; Clackson,
T.; Frame, M.; Brunton, V.; Sawyer, T. Structure-based Methods
to Design Potent and Selective Src/Abl Dual Inhibitors and their
Development as Antitumor and Antimetastatic Agents. Proceed-
ings of the 226th American Chemical Society National Meeting;
New York, Sept 7-11, 2003; American Chemical Society: Wash-
ington, D.C., 2003; COMP-079.
(15) Nagar, B.; Bornmann, W. G.; Pellicena, P.; Schindler, T.; Veach,
D. R.; Miller, W. T.; Clarkson, B.; Kuriyan, J . Crystal Structures
of the Kinase Domain of c-Abl in Complex with the Small
Molecule Inhibitors PD173955 and Imatinib (STI-571). Cancer
Res. 2002, 62, 4236-4243.
(16) Boschelli, D. H.; Ye, F.; Wang, Y. D.; Dutia, M.; J ohnson, S. L.;
Wu, B.; Miller, K.; Powell, D. W.; Yaczko, D.; Young, M.; Tischler,
M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J .; Grod, J .;
Lucas, J .; Weber, J . M.; Boschelli, F. Optimization of 4-Phenyl-
amino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase
Activity. J . Med. Chem. 2001, 44, 3965-3977.
(17) Boschelli, D. H.; Ye, F.; Wu, B.; Wang, Y. D.; Barrios Sosa, A.
C.; Yaczko, D.; Powell, D.; Golas, J . M.; Lucas, J .; Boschelli, F.
Investigation of the Effect of Varying the 4-Anilino and 7-Alkoxy
(30) O’Hare, T.; Stoffregen, E. P.; Abdullah, O. M.; Deininger, M. W.;
Rivera, V. M.; Tang, H.; Keats, J .; Metcalf, C., III; Wang, Y.;
Sundaramoorthi, R.; Shakespeare, W.; Dalgarno, D. C.; Sawyer,
T.; Druker, B. J . Potent Inhibition of Imatinib-Resistant Variants
of Bcr-Abl by a Novel Dual Selective Src/Abl Kinase Inhibitor
AP23464: Implications for CML Therapy. Blood 2003, 102 (111),
Abstract 59.
(31) Warmuth, M.; Damoiseaux, R.; Liu, Y.; Fabbro, D.; Gray, N. Src
Family Kinases: Potential Targets for the Treatment of Human
Cancer and Leukemia. Curr. Pharm. Des. 2003, 9, 2043-2059.
(32) Roginskaya, V.; Zuo, S.; Caudell, E.; Nambudiri, G.; Kraker, A.
J .; Corey, S. J . Therapeutic Targeting of Src-kinase Lyn in
Myeloid Leukemic Cell Growth. Leukemia 1999, 13, 855-861.
(33) Warmuth, M.; Bergmann, M.; Priess, A.; Hauslmann, K.; Em-
merich, B.; Hallek, M. The Src Family Kinase Hck Interacts with
Bcr-Abl by a Kinase-Independent Mechanism and Phosphoryl-
ates the Grb2-Binding Site of Bcr. J . Biol. Chem. 1997, 272,
33260-33270.
(34) Lionberger, J . M.; Wilson, M. B.; Smithgall, T. E. Transformation
of Myeloid Leukemia Cells to Cytokine Independence by Bcr-
Abl is Suppressed by Kinase-Defective Hck. J . Biol. Chem. 2000,
275, 18581-18585.
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