9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: Design, synthesis, and biological evaluation

Journal of Medicinal Chemistry

Volumn 52, Issue 15, 2009, Pages 4743-4756

  Huang, Wei Sheng ^a   Zhu, Xiaotian ^a   Wang, Yihan ^a   Azam, Mohammad ^b,c   Wen, David ^a   Sundaramoorthi, Raji ^a   Thomas, R Mathew ^a   Liu, Shuangying ^a   Banda, Geetha ^a   Lentini, Scott P ^a   Das, Sasmita ^a   Xu, Qihong ^a   Keats, Jeff ^a   Wang, Frank ^a   Wardwell, Scott ^a   Ning, Yaoyu ^a   Snodgrass, Joseph T ^a   Broudy, Marc I ^a   Russian, Karin ^a   Daley, George Q ^b,c   Iuliucci, John ^a   Dalgarno, David C ^a   Clackson, Tim ^a   Sawyer, Tomi K ^a   Shakespeare, William C ^a   more..

^a ARIAD PHARMACEUTICALS INC   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [2 [6 (CYCLOPROPYLAMINO) 9H PURIN 9 YL]VINYL] 4 METHYL N [3 (4 METHYL 1 IMIDAZOL 1 YL) 5 (TRIFLUOROMETHYL)PHENYL]BENZAMIDE; 3 [2 [6 (CYCLOPROPYLAMINO) 9H PURIN 9 YL]VINYL] 4 METHYL N [4 (TRIFLUOROMETHYL)PYRIDIN 2 YL]BENZAMIDE; AP 24163; AP 24226; NILOTINIB; PROTEIN TYROSINE KINASE INHIBITOR; PURINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER SURVIVAL; CHRONIC MYELOID LEUKEMIA; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME CONFORMATION; ENZYME INACTIVATION; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; TUMOR REGRESSION; TUMOR XENOGRAFT;

ANIMALS; DRUG DESIGN; FEMALE; HUMANS; K562 CELLS; MICE; NIH 3T3 CELLS; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-ABL; PURINES; RATS; SRC-FAMILY KINASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68549115413     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900166t     Document Type: Article

References (67)

1. Nowell, P. C.; Hungerford, D. A. A minute chromosome in chronic granulocytic leukemia. Science 1960, 132, 1497-1501.
2. (a) Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973, 243, 290-293.
3. (b) Groffen, J; Stephenson, J. R.; Heisterkamp, N.; de Klein, A.; Bartram, C. R.; Grosveld, G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984, 36, 93-99.
4. (a) Lugo, T. G.; Pendergast, A. M.; Muller, A. J.; Witte, O. N. Tyrosine kinase activity and transformation potency of Bcr-Abl oncogene products. Science 1990, 247, 1079-1082.
5. (b) Sawyers, C. L. Chronic myeloid leukemia. N. Engl. J. Med. 1999, 340, 1330-1340.
6. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Discovery 2002, 1, 493-502.
7. Weisberg, E.; Manley, P. W.; Cowan-Jacob, S. W.; Hochhaus, A.; Griffin, J. D. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukemia. Nat. Rev. Cancer 2007, 7, 345-356.
8. (a) Shah, N. P.; Tran, C.; Lee, F. Y.; Chen, P.; Norris, D.; Sawyers, C. L. Overriding imatinib resistance with a novel Abl kinase inhibitor. Science 2004, 305, 399-402.
9. (b) 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. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005, 65, 4500-4505.
10. (c) O'Hare, T.; Eide, C. A.; Deininger, M. W. N. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007, 110, 2242-2249.
11. (d) O'Hare, T.; Eide, C. A.; Deininger, M. W. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. Exp. Opin. Invest. Drugs 2008, 17, 865-878.
12. (e) Lee, F.; Fandi, A.; Voi, M. Overcoming kinase resistance in chronic myeloid leukemia. Int. J. Biochem. Cell Biol. 2008, 40, 334-343.
13. (f) Tanaka, R.; Kimura, S. Abl tyrosine kinase inhibitors for overriding Bcr-Abl/ T315I: from the second to third generation. Exp. Rev. Anticancer Ther. 2008, 8, 1387-1398.
14. (g) Noronha, G.; Cao, J.; Chow, C. P.; Dneprovskaia, E.; Fine, R. M.; Hood, J.; Kang, X.; Klebansky, B.; Lohse, D.; Mak, C. C.; McPherson, A.; Palanki, M. S. S.; Pathak, V. P.; Renick, J.; Soll, R.; Zeng, B. Inhibitors of ABL and the ABL- T315I mutation. Curr. Top. Med. Chem 2008, 8, 905-921.
15. (h) Quintas-Cardama, A.; Cortes, J. Therapeutic options against BCR-ABL1 T315I -positive chronic myelogenous leukemia. Clin. Cancer Res. 2008, 14, 4392-4399.
16. (a) Mahon, F.-X.; Hayette, S.; Lagarde, V.; Belloc, F.; Turcq, B.; Nicolini, F.; Belanger, C.; Manley, P. W.; Leroy, C.; Etienne, G.; Roche, S.; Pasquet, J.-M. Evidence that resistance to nilotinib may be due to Bcr-Abl, Pgp, or Src kinase overexpression. Cancer Res. 2008, 68, 9809-9816.
17. (b) Schenone, S.; Manetti, F.; Botta, M. Last findings on dual inhibitors of Abl and Src tyrosine-kinases. Mini-Rev. Med. Chem. 2007, 7, 191-201.
18. (c) Kantarjian, H. M.; Giles, F.; Quintas-Cardama, A.; Cortes, J. Important therapeutic targets in chronic myelogenous leukemia. Clin. Cancer Res. 2007, 13, 1089-1097.
19. (d) Martinelli, G.; Soverini, S.; Rosti, G.; Baccarani, M. Dual tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia 2005, 19, 1872-1879.
20. Hu, Y.; Liu, Y.; Pelletier, S.; Buchdunger, E.; Warmuth, M.; Fabbro, D.; Hallek, M.; Van Etten, R. A.; Li, S. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat. Genet. 2004, 36, 453-461.
21. (a) Srinivasan, D.; Plattner, R. Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res. 2006, 66, 5648-5655.
22. (b) Srinivasan, D.; Sims, J. T.; Plattner, R. Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival. Oncogene 2008, 27, 1095-1105.
23. Lin, J.; Arlinghaus, R. Activated c-Abl tyrosine kinase in malignant solid tumors. Oncogene 2008, 27, 4385-4391.
24. (a) Park, S. I.; Shah, A. N.; Zhang, J.; Gallick, G. E. Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors. Expert Opin. Ther. Targets 2007, 11, 1207-1217.
25. (b) Summy, J. M.; Gallick, G. E. Treatment for advanced tumors: Src reclaims center stage. Clin. Cancer Res. 2006, 12, 1398-1401.
26. (c) Chen, T.; George, J. A.; Taylor, C. C. Src tyrosine kinase as a chemotherapeutic target: is there a clinical case?. Anti-Cancer Drugs 2006, 17, 123-131.
27. (d) Alvarez, R. H.; Kantarjian, H. M.; Cortes, J. E. The role of Src in solid and hematologic malignancies: development of new-generation Src inhibitors. Cancer 2006, 107, 1918-1929.
28. (e) Lesslie, D. P.; Gallick, G. E. Src family kinases as regulators of angiogenesis: therapeutic implications. Curr. Cancer Ther. Rev. 2005, 1, 45-50.
29. (f) Tsygankov, A. Y.; Shore, S. K. Src: regulation, role in human carcinogenesis and pharmacological inhibitors. Curr. Pharm. Des. 2004, 10, 1745-1756.
30. (g) Yeatman, T. J. A renaissance for Src. Nat. Rev. Cancer 2004, 4, 470-480.
31. Lombardo, L. J.; Lee, F. Y.; Chen, P.; Norris, D.; Barrish, J. C.; Behnia, K.; Castaneda, S.; Cornelius, L. A. M.; Das, J.; Doweyko, A. M.; Fairchild, C.; Hunt, J. T.; Inigo, I.; Johnston, K.; Kamath, A.; Kan, D.; Klei, H.; Marathe, P.; Pang, S.; Peterson, R.; Pitt, S.; Schieven, G. L.; Schmidt, R. J.; Tokarski, J.; Wen, M.-L.; Wityak, J.; Borzilleri, R. M. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem. 2004, 47, 6658-6661.
32. (a) Boschelli, D. H.; Ye, F.; Wang, Y. D.; Dutia, M.; Johnson, 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-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J. Med. Chem. 2001, 44, 3965-3977.
33. (b) Hennequin, L. F.; Allen, J.; Breed, J.; Curwen, J.; Fennell, M.; Green, T. P.; Lambert-van der Brempt, C.; Morgentin, R.; Norman, R. A.; Olivier, A.; Otterbein, L.; Ple, P. A.; Warin, N.; Costello, G. N-(5-Chloro-1,3- benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem. 2006, 49, 6465-6488.
34. Fabian, M. A.; Biggs, W. H.; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lelias, J.-M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 2005, 23, 329-336.
35. (a) Schindler, T.; Bornmann, W.; Pellicena, P.; Miller, W. T.; Clarkson, B.; Kuriyan, J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000, 289, 1938-1942.
36. (b) Mol, C. D.; Fabbro, D.; Hosfield, D. J. Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors. Curr. Opin. Drug Discovery Dev. 2004, 7, 639-648.
37. (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. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005, 7, 129-141.
38. (b) Golemovic, M.; Verstovsek, S.; Giles, F.; Cortes, J.; Manshouri, T.; Manley, P. W.; Mestan, J.; Dugan, M.; Alland, L.; Griffin, J. D.; Arlinghaus, R. B.; Sun, T.; Kantarjian, H.; Beran, M. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin. Cancer Res. 2006, 11, 4941-4947.
39. (c) Manley, P. W.; Cowan-Jacob, S. W.; Mestan, J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim. Biophys. Acta, Proteins Proteomics 2005, 1754, 3-13.
40. (a) Horio, T.; Hamasaki, T.; Inoue, T.; Wakayama, T.; Itou, S.; Naito, H.; Asaki, T.; Hayase, H.; Niwa, T. Structural factors contributing to the Abl/Lyn dual inhibitory activity of 3-substituted benzamide derivatives. Bioorg. Med. Chem. Lett. 2007, 17, 2712-2717.
41. (b) Asaki, T.; Sugiyama, Y.; Hamamoto, T.; Higashioka, M.; Umehara, M.; Naito, H.; Niwa, T. Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 1421-1425.
42. (c) Kimura, S.; Naito, H.; Segawa, H.; Kuroda, J.; Yuasa, T.; Sato, K.; Yokota, A.; Kamitsuji, Y.; Kawata, E.; Ashihara, E.; Nakaya, Y.; Naruoka, H.; Wakayama, T.; Nasu, K.; Asaki, T.; Niwa, T.; Hirabayashi, K.; Maekawa, T. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 2005, 106, 3948-3954.
43. (a) Lowinger, T. B.; Riedl, B.; Dumas, J.; Smith, R. A. Design and discovery of small molecules targeting Raf-1 kinase. Curr. Pharm. Des. 2002, 8, 2269-2278.
44. (b) 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.
45. 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.
46. Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease, L. J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D. R.; Davidsen, S. K.; Michaelides, M. R. Discovery of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N′-(2-fluoro-5-methylphenyl) urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J. Med. Chem. 2007, 50, 1584-1597.
47. (a) O'Hare, T.; Pollock, R.; Stoffregen, E. P.; Keats, J. A.; Abdullah, O. M.; Moseson, E. M.; Rivera, V. M.; Tang, H.; Metcalf, C. A.III; Bohacek, R. S.; Wang, Y.; Sundaramoorthi, R.; Shakespeare, W. C.; Dalgarno, D.; Clackson, T.; Sawyer, T. K.; Deininger, M. W.; Druker, B. J. Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 2004, 104, 2532-2539.
48. (b) Azam, M.; Nardi, V.; Shakespeare, W. C.; Metcalf, C. A.III; Bohacek, R. S.; Wang, Y.; Sundaramoorthi, R.; Sliz, P.; Veach, D. R.; Bornmann, W. G.; Clarkson, B.; Dalgarno, D. C.; Sawyer, T. K.; Daley, G. Q. Activity of dual Src-Abl inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 9244-9249.
49. Wang, Y.; Shakespeare, W. C.; Huang, W.-S.; Sundaramoorthi, R.; Lentini, S.; Das, S.; Liu, S.; Banda, G.; Wen, D.; Zhu, X.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Dalgarno, D.; Clackson, T.; Sawyer, T. K. Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 4907-4912.
50. (a) Liu, Y.; Gray, N. S. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2006, 2, 358-364.
51. (b) Okram, B.; Nagle, A.; Adrian, F. J.; Lee, C.; Ren, P.; Wang, X.; Sim, T.; Xie, Y.; Wang, X.; Xia, G.; Spraggon, G.; Warmuth, M.; Liu, Y.; Gray, N. S. A general strategy for creating "inactive-conformation" Abl inhibitors. Chem. Biol. 2006, 13, 779-786.
52. Sherman, W.; Day, T.; Jacobson, M. P.; Friesner, R. A.; Farid, R. Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem. 2006, 49, 534-553.
53. Dalgarno, D.; Stehle, T.; Narula, S.; Schelling, P.; van Schravendijk, M. R.; Adams, S.; Andrade, L.; Keats, J.; Ram, M.; Jin, L.; Grossman, T.; MacNeil, I.; Metcalf, C.III; Shakespeare, W.; Wang, Y.; Keenan, T.; Sundaramoorthi, R.; Bohacek, R.; Weigele, M.; Sawyer, T. Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds. Chem. Biol. Drug Des. 2006, 67, 46-57.
54. Boesen, T.; Madsen, C.; Henriksen, U.; Dahl, O. Preparation of N-(alk-1-enyl) nucleobase compounds by Horner and Horner-Wadsworth-Emmons reactions. J. Chem. Soc., Perkin Trans. 1 2000, 2015-2021.
55. Huang, W.-S.; Wang, Y.; Sundaramoorthi, R.; Thomas, R. M.; Wen, D.; Liu, S.; Lentini, S. P.; Das, S.; Banda, G.; Sawyer, T. K.; Shakespeare, W. C. Facile synthesis of 9-(arenethenyl)purines via Heck reaction of 9-vinylpurines and aryl halides. Tetrahedron Lett. 2007, 48, 7388-7391.
56. Pitha, J.; Ts'o, P. O. P. N-Vinyl derivatives of substituted pyrimidines and purines. J. Org. Chem. 1968, 33, 1341-1344.
57. Huang, W.-S.; Shakespeare, W. C. An efficient synthesis of nilotinib (AMN107). Synthesis 2007, 2121-2124 and references cited therein.
58. Pierce, A. C.; ter Haar, E.; Binch, H. M.; Kay, D. P.; Patel, S. R.; Li, P.CH⋯O and CH⋯N hydrogen bonds in ligand design:Anovel quinazolin-4-ylthiazol-2-ylamine protein kinase inhibitor. J. Med. Chem. 2005, 48, 1278-1281 and references cited therein.
59. Daylight Chemical Information System, Inc. http://www.daylight.com, accessed March 2005.
60. (a) Seeliger, M. A.; Nagar, B.; Frank, F.; Cao, X.; Henderson, M. N.; Kuriyan, J. c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure 2007, 15, 299-311.
61. (b) Levinson, N. M.; Kuchment, O.; Shen, K.; Young, M. A.; Koldobskiy, M.; Karplus, M.; Cole, P. A.; Kuriyan, J. A Src-like inactive conformation in the Abl tyrosine kinase domain. PLoS Biol. 2006, 4, 753-767.
62. (c) 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.
63. (d) Cowan-Jacob, S. W.; Fendrich, G.; Manley, P. W.; Jahnke, W.; Fabbro, D.; Liebetanz, J.; Meyer, T. The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. Structure 2005, 13, 861-871.
64. Dar, A. C.; Lopez, M. S.; Shokat, K. M. Small molecule recognition of c-Src via the Imatinib-binding conformation. Chem. Biol. 2008, 15, 1015-1022.
65. DiMauro, E. F.; Newcomb, J.; Nunes, J. J.; Bemis, J. E.; Boucher, C.; Buchanan, J. L.; Buckner, W. H.; Cee, V. J.; Chai, L.; Deak, H. L.; Epstein, L.; Faust, T.; Gallant, P.; Geuns-Meyer, S. D.; Gore, A.; Gu, Y.; Henkle, B.; Hodous, B. L.; Hsieh, F.; Huang, X.; Kim, J. L.; Lee, J.; 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.; Welcher, A. A.; White, R. D.; Zhao, H.; Zhu, L.; Zhu, X. Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: Synthesis, SAR, and in vivo anti-inflammatory activity. J. Med. Chem. 2006, 49, 5671-5686.
66. Azam, M. et al. Unpublished results.
67. Wang, Y.; Huang, W.-S.; Sundaramoorthi, R.; Zhu, X.; Thomas, R. M.; Shakespeare, W. C.; Dalgarno, D. C.; Sawyer, T. K. Preparation of purine heterocyclic derivatives as kinase inhibitors for therapeutic use as anticancer agents. PCT Int. Appl. WO 2007021937, 2007.