Features of selective kinase inhibitors

Chemistry and Biology

Volumn 12, Issue 6, 2005, Pages 621-637

  Knight, Zachary A ^b   Shokat, Kevan M ^a,c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PHOSPHATASE; PROTEIN KINASE INHIBITOR;

ANIMAL; CHEMISTRY; DRUG SCREENING; ENZYME SPECIFICITY; HUMAN; METABOLISM; REVIEW;

ANIMALS; DRUG EVALUATION, PRECLINICAL; HUMANS; PHOSPHORIC MONOESTER HYDROLASES; PROTEIN KINASE INHIBITORS; SUBSTRATE SPECIFICITY;

EID: 24944497371     PISSN: 10745521     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.chembiol.2005.04.011     Document Type: Review

References (130)

1. Druker, B.J. (2004). Molecularly targeted therapy: have the floodgates opened? Oncologist 9, 357-360.
2. Cohen, P. (1999). The development and therapeutic potential of protein kinase inhibitors. Curr. Opin. Chem. Biol. 3, 459-465.
3. Pargellis, C., Tong, L., Churchill, L., Cirillo, P.F., Gilmore, T., Graham, A.G., Grob, P.M., Hickey, E.R., Moss, N., Pav, S., et al. (2002). Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol. 9, 268-272.
4. Barnett, S.F., Defeo-Jones, D., Fu, S., Hancock, P.J., Haskell, K.M., Jones, R.E., Kahana, J.A., Kral, A.M., Leander, K., Lee, L.L., et al. (2004). Identification and characterization of pleckstrin homology domain dependent and isozyme specific Akt inhibitors. Biochem. J. 385, 399-408. Published online September 29, 2004. 10.1042/BJ20040849
5. Burke, J.R., Pattoli, M.A., Gregor, K.R., Brassil, P.J., MacMaster, J.F., McIntyre, K.W., Yang, X., Iotzova, V.S., Clarke, W., Strnad, J., et al. (2003). BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J. Biol. Chem. 278, 1450-1456.
6. Arnold, L.D., Calderwood, D.J., Dixon, R.W., Johnston, D.N., Kamens, J.S., Munschauer, R., Rafferty, P., and Ratnofsky, S.E. (2000). Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I. Bioorg. Med. Chem. Lett. 10, 2167-2170.
7. Sadhu, C., Dick, K., Tino, W.T., and Staunton, D.E. (2003). Selective role of PI3K delta in neutrophil inflammatory responses. Biochem. Biophys. Res. Commun. 308, 764-769.
8. Changelian, P.S., Flanagan, M.E., Ball, D.J., Kent, C.R., Magnuson, K.S., Martin, W.H., Rizzuti, B.J., Sawyer, P.S., Perry, B.D., Brissette, W.H., et al. (2003). Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302, 875-878.
9. Lin, T.A., McIntyre, K.W., Das, J., Liu, C., O'Day, K.D., Penhallow, B., Hung, C.Y., Whitney, G.S., Shuster, D.J., Yang, X., et al. (2004). Selective Itk inhibitors block T-cell activation and murine lung inflammation. Biochemistry 43, 11056-11062.
10. Cheng, Y., and Prusoff, W.H. (1973). Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099-3108.
11. Traut, T.W. (1994). Physiological concentrations of purines and pyrimidines. Mol. Cell. Biochem. 140, 1-22.
12. Gribble, F.M., Loussouarn, G., Tucker, S.J., Zhao, C., Nichols, C.G., and Ashcroft, F.M. (2000). A novel method for measurement of submembrane ATP concentration. J. Biol. Chem. 275, 30046-30049.
13. Knight, Z.A., Chiang, G.G., Alaimo, P.J., Kenski, D.M., Ho, C.B., Coan, K., Abraham, R.T., and Shokat, K.M. (2004). Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg. Med. Chem. 12, 4749-4759.
14. Dennis, P.B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S.C., and Thomas, G. (2001). Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102-1105.
15. Downing, G.J., Kim, S., Nakanishi, S., Catt, K.J., and Balla, T. (1996). Characterization of a soluble adrenal phosphatidylinositol 4-kinase reveals wortmannin sensitivity of type III phosphatidylinositol kinases. Biochemistry 35, 3587-3594.
16. Zhao, X.H., Bondeva, T., and Balla, T. (2000). Characterization of recombinant phosphatidylinositol 4-kinase beta reveals auto- and heterophosphorylation of the enzyme. J. Biol. Chem. 275, 14642-14648.
17. Suer, S., Sickmann, A., Meyer, H.E., Herberg, F.W., and Heilmeyer, L.M., Jr. (2001). Human phosphatidylinositol 4-kinase isoform PI4K92. Expression of the recombinant enzyme and determination of multiple phosphorylation sites. Eur. J. Biochem. 268, 2099-2106.
18. Hawkins, J., Zheng, S., Frantz, B., and LoGrasso, P. (2000). p38 map kinase substrate specificity differs greatly for protein and peptide substrates. Arch. Biochem. Biophys. 382, 310-313.
19. Tian, G., Kane, L.S., Holmes, W.D., and Davis, S.T. (2002). Modulation of cyclin-dependent kinase 4 by binding of magnesium (II) and manganese (II). Biophys. Chem. 95, 79-90.
20. Sondhi, D., Xu, W., Songyang, Z., Eck, M.J., and Cole, P.A. (1998). Peptide and protein phosphorylation by protein tyrosine kinase Csk: insights into specificity and mechanism. Biochemistry 37, 165-172.
21. Schindler, T., Bornmann, W., Pellicena, P., Miller, W.T., Clarkson, B., and Kuriyan, J. (2000). Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938-1942.
22. Wan, P.T., 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., et al. (2004). Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855-867.
23. Frantz, B., Klatt, T., Pang, M., Parsons, J., Rolando, A., Williams, H., Tocci, M.J., O'Keefe, S.J., and O'Neill, E.A. (1998). The activation state of p38 mitogen-activated protein kinase determines the efficiency of ATP competition for pyridinylimidazole inhibitor binding. Biochemistry 37, 13846-13853.
24. Kendall, R.L., Rutledge, R.Z., Mao, X., Tebben, A.J., Hungate, R.W., and Thomas, K.A. (1999). Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues. J. Biol. Chem. 274, 6453-6460.
25. Parast, C.V., Mroczkowski, B., Pinko, C., Misialek, S., Khambatta, G., and Appelt, K. (1998). Characterization and kinetic mechanism of catalytic domain of human vascular endothelial growth factor receptor-2 tyrosine kinase (VEGFR2 TK), a key enzyme in angiogenesis. Biochemistry 37, 16788-16801.
26. Sadler, T.M., Achilleos, M., Ragunathan, S., Pitkin, A., La-Rocque, J., Morin, J., Annable, R., Greenberger, L.M., Frost, P., and Zhang, Y. (2004). Development and comparison of two nonradioactive kinase assays for I kappa B kinase. Anal. Biochem. 326, 106-113.
27. Li, J., Peet, G.W., Pullen, S.S., Schembri-King, J., Warren, T.C., Marcu, K.B., Kehry, M.R., Barton, R., and Jakes, S. (1998). Recombinant IkappaB kinases alpha and beta are direct kinases of Ikappa Balpha. J. Biol. Chem. 273, 30736-30741.
28. Mercuric, F., Murray, B.W., Shevchenko, A., Bennett, B.L., Young, D.B., Li, J.W., Pascual, G., Motiwala, A., Zhu, H., Mann, M., et al. (1999). IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mol. Cell. Biol. 19, 1526-1538.
29. Kishore, N., Huynh, Q.K., Mathialagan, S., Hall, T., Rouw, S., Creely, D., Lange, G., Caroll, J., Reitz, B., Donnelly, A., et al. (2002). IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. J. Biol. Chem. 277, 13840-13847.
30. Huynh, Q.K., Boddupalli, H., Rouw, S.A., Koboldt, C.M., Hall, T., Sommers, C., Hauser, S.D., Pierce, J.L., Combs, R.G., Reitz, B.A., et al. (2000). Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity. J. Biol. Chem. 275, 25883-25891.
31. Wisniewski, D., LoGrasso, P., Calaycay, J., and Marcy, A. (1999). Assay for IkappaB kinases using an in vivo biotinylated IkappaB protein substrate. Anal. Biochem. 274, 220-228.
32. Flint, N.A., Amrein, K.E., Jascur, T., and Burn, P. (1994). Purification and characterization of an activated form of the protein tyrosine kinase Lck from an Escherichia coli expression system. J. Cell. Biochem. 55, 389-397.
33. Schmid, A.C., Byrne, R.D., Vilar, R., and Woscholski, R. (2004). Bisperoxovanadium compounds are potent PTEN inhibitors. FEBS Lett. 566, 35-38.
34. Mustelin, T., Alonso, A., Bottini, N., Huynh, H., Rahmouni, S., Nika, K., Louis-dit-Sully, C., Tautz, L., Togo, S.H., Bruckner, S., Mena-Duran, A.V., and al-Khouri, A.M. (2004). Protein tyrosine phosphatases in T cell physiology. Mol. Immunol. 41, 687-700.
35. Ferrell, J.E., Jr. (1996). Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem. Sci. 21, 460-466.
36. Huang, C.Y., and Ferrell, J.E., Jr. (1996). Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA 93, 10078-10083.
37. Tengholm, A., and Meyer, T. (2002). A PI3-kinase signaling code for insulin-triggered insertion of glucose transporters into the plasma membrane. Curr. Biol. 12, 1871-1876.
38. Kohler, K., Lellouch, A.C., Vollmer, S., Stoevesandt, O., Hoff, A., Peters, L., Rogl, H., Malissen, B., and Brock, R. (2005). Chemical inhibitors when timing is critical: a pharmacological concept for the maturation of T cell contacts. ChemBioChem 6, 152-161.
39. Rogers, B., Decottignies, A., Kolaczkowski, M., Carvajal, E., Balzi, E., and Goffeau, A. (2001). The pleitropic drug ABC transporters from Saccharomyces cerevisiae. J. Mol. Microbiol. Biotechnol. 3, 207-214.
40. Stein, W.D. (1998). Kinetics of the P-glycoprotein, the multidrug transporter. Exp. Physiol. 83, 221-232.
41. Wohlbold, L., van der Kuip, H., Miething, C., Vornlocher, H.P., Knabbe, C., Duyster, J., and Aulitzky, W.E. (2003). Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood 102, 2236-2239.
42. Ghaemmaghami, S., Huh, W.K., Bower, K., Howson, R.W., Belle, A., Dephoure, N., O'Shea, E.K., and Weissman, J.S. (2003). Global analysis of protein expression in yeast. Nature 425, 737-741.
43. Sherman, F. (1991). Guide to Yeast Genetics and Molecular Biology, Volume 194 (San Diego: Academic Press).
44. Bhatt, R.R., and Ferrell, J.E., Jr. (2000). Cloning and characterization of Xenopus Rsk2, the predominant p90 Rsk isozyme in oocytes and eggs. J. Biol. Chem. 275, 32983-32990.
45. Arooz, T., Yam, C.H., Siu, W.Y., Lau, A., Li, K.K., and Poon, R.Y. (2000). On the concentrations of cyclins and cyclin-dependent kinases in extracts of cultured human cells. Biochemistry 39, 9494-9501.
46. Lipinski, C.A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44, 235-249.
47. Lipinski, C., and Hopkins, A. (2004). Navigating chemical space for biology and medicine. Nature 432, 855-861.
48. Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeny, P.J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3-25.
49. Veber, D.F., Johnson, S.R., Cheng, H.Y., Smith, B.R., Ward, K.W., and Kopple, K.D. (2002). Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615-2623.
50. Noble, M.E., Endicott, J.A., and Johnson, L.N. (2004). Protein kinase inhibitors: insights into drug design from structure. Science 303, 1800-1805.
51. McGovern, S.L., Helfand, B.T., Feng, B., and Shoichet, B.K. (2003). A specific mechanism of nonspecific inhibition. J. Med. Chem. 46, 4265-4272.
52. Ramdas, L., McMurray, J.S., and Budde, R.J. (1994). The degree of inhibition of protein tyrosine kinase activity by tyrphostin 23 and 25 is related to their instability. Cancer Res. 54, 867-869.
53. Ramdas, L., Obeyesekere, N.U., McMurray, J.S., Gallick, G.E., Seifert, W.E., Jr., and Budde, R.J. (1995). A tyrphostin-derived inhibitor of protein tyrosine kinases: isolation and characterization. Arch. Biochem. Biophys. 323, 237-242.
54. Ramdas, L., and Budde, R.J. (1998). The instability of polyhydroxylated aromatic protein tyrosine kinase inhibitors in the presence of manganese. Cancer Biochem. Biophys. 16, 375-385.
55. McGovern, S.L., and Shoichet, B.K. (2003). Kinase inhibitors: not just for kinases anymore. J. Med. Chem. 46, 1478-1483.
56. Holleran, J.L., Egorin, M.J., Zuhowski, E.G., Parise, R.A., Musser, S.M., and Pan, S.S. (2003). Use of high-performance liquid chromatography to characterize the rapid decomposition of wortmannin in tissue culture media. Anal. Biochem. 323, 19-25.
57. Duncia, J.V., Santella, J.B., III, Higley, C.A., Pitts, W.J., Wityak, J., Frietze, W.E., Rankin, F.W., Sun, J.H., Earl, R.A., Tabaka, A.C., et al. (1998). MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg. Med. Chem. Lett. 8, 2839-2844.
58. Rishton, G.M. (2003). Nonleadlikeness and leadlikeness in biochemical screening. Drug Discov. Today 8, 86-96.
59. Fry, D.W., Bridges, A.J., Denny, W.A., Doherty, A., Greis, K.D., Hicks, J.L., Hook, K.E., Keller, P.R., Leopold, W.R., Loo, J.A., et al. (1998). Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc. Natl. Acad. Sci. USA 95, 12022-12027.
60. Vieth, M., Higgs, R.E., Robertson, D.H., Shapiro, M., Gragg, E.A., and Hemmerle, H. (2004). Kinomics-structural biology and chemogenomics of kinase inhibitors and targets. Biochim. Biophys. Acta 1697, 243-257.
61. Yamamoto, N., Takeshita, K., Shichijo, M., Kokubo, T., Sato, M., Nakashima, K., Ishimori, M., Nagai, H., Li, Y.F., Yura, T., et al. (2003). The orally available spleen tyrosine kinase inhibitor 2-[7-(3,4-dimethoxyphenyl)- imidazo[1,2-c]pyrimidin-5-ylamino] nicotinamide dihydrochloride (BAY 61-3606) blocks antigen-induced airway inflammation in rodents. J. Pharmacol. Exp. Ther. 306, 1174-1181.
62. Bain, J., McLauchlan, H., Elliott, M., and Cohen, P. (2003). The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199-204.
63. Davies, S.P., Reddy, H., Caivano, M., and Cohen, P. (2000). Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95-105.
64. Liu, Y., Bishop, A., Witucki, L., Kraybill, B., Shimizu, E., Tsien, J., Ubersax, J., Blethrow, J., Morgan, D.O., and Shokat, K.M. (1999). Structural basis for selective inhibition of Src family kinases by PP1. Chem. Biol. 6, 671-678.
65. Blencke, S., Zech, B., Engkvist, O., Greff, Z., Orfi, L., Horvath, Z., Keri, G., Ullrich, A., and Daub, H. (2004). Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors. Chem. Biol. 11, 691-701.
66. Godl, K., Wissing, J., Kurtenbach, A., Habenberger, P., Blencke, S., Gutbrod, H., Salassidis, K., Stein-Gerlach, M., Missio, A., Cotten, M., et al. (2003). An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proc. Natl. Acad. Sci. USA 100, 15434-15439.
67. Frye, S.V. (1999). Structure-activity relationship homology (SARAH): a conceptual framework for drug discovery in the genomic era. Chem. Biol. 6, R3-R7.
68. Leahy, J.J., Golding, B.T., Griffin, R.J., Hardcastle, I.R., Richardson, C., Rigoreau, L., and Smith, G.C. (2004). Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg. Med. Chem. Lett. 14, 6083-6087.
69. Wissing, J., Godl, K., Brehmer, D., Blencke, S., Weber, M., Habenberger, P., Stein-Gerlach, M., Missio, A., Cotten, M., Muller, S., et al. (2004). Chemical proteomic analysis reveals alternative modes of action for pyrido[2,3-d]pyrimidine kinase inhibitors. Mol. Cell. Proteomics 3, 1181-1193.
70. Knockaert, M., Gray, N., Damiens, E., Chang, Y.T., Grellier, P., Grant, K., Fergusson, D., Mottram, J., Soete, M., Dubremetz, J.F., et al. (2000). Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors. Chem. Biol. 7, 411-422.
71. Knockaert, M., Wieking, K., Schmitt, S., Leost, M., Grant, K.M., Mottram, J.C., Kunick, C., and Meijer, L. (2002). Intracellular targets of paullones. Identification following affinity purification on immobilized inhibitor. J. Biol. Chem. 277, 25493-25501.
72. Knockaert, M., Lenormand, P., Gray, N., Schultz, P., Pouyssegur, J., and Meijer, L. (2002). p42/p44 MAPKs are intracellular targets of the CDK inhibitor purvalanol. Oncogene 21, 6413-6424.
73. Rosania, G.R., Merlie, J., Jr., Gray, N., Chang, Y.T., Schultz, P.G., and Heald, R. (1999). A cyclin-dependent kinase inhibitor inducing cancer cell differentiation: biochemical identification using Xenopus egg extracts. Proc. Natl. Acad. Sci. USA 96, 4797-4802.
74. Brehmer, D., Godl, K., Zech, B., Wissing, J., and Daub, H. (2004). Proteome-wide identification of cellular targets affected by bisindolylmaleimide-type protein kinase C inhibitors. Mol. Cell. Proteomics 3, 490-500.
75. Wissing, J., Godl, K., Brehmer, D., Blencke, S., Weber, M., Habenberger, P., Stein-Gerlach, M., Missio, A., Cotten, M., Muller, S., et al. (2004). Chemical proteomic analysis reveals alternative modes of action for pyrido[2,3-d]pyrimidine kinase inhibitors. Mol. Cell. Proteomics 3, 1181-1193.
76. Ding, S., Wu, T.Y., Brinker, A., Peters, E.C., Hur, W., Gray, N.S., and Schultz, P.G. (2003). Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. USA 100, 7632-7637.
77. Liu, Y., Shreder, K.R., Gai, W., Corral, S., Ferris, D.K., and Rosenblum, J.S. (2005). Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase. Chem. Biol. 12, 99-107.
78. Abbott, B.M., and Thompson, P.E. (2004). PDE2 inhibition by the PI3 kinase inhibitor LY294002 and analogues. Bioorg. Med. Chem. Lett. 14, 2847-2851.
79. Welling, A., Hofmann, F., and Wegener, J.W. (2004). Inhibition of L-type Cav1.2 Ca2+ channels by LY294002 and Go6983. Mol. Pharmacol. 67, 541-544.
80. Sun, H., Oudit, G.Y., Ramirez, R.J., Costantini, D., and Backx, P.H. (2004). The phosphoinositide 3-kinase inhibitor LY294002 enhances cardiac myocyte contractility via a direct inhibition of Ik,slow currents. Cardiovasc. Res. 62, 509-520.
81. Pasapera Limon, A.M., Herrera-Munoz, J., Gutierrez-Sagal, R., and Ulloa-Aguirre, A. (2003). The phosphatidylinositol 3-kinase inhibitor LY294002 binds the estrogen receptor and inhibits 17beta-estradiol-induced transcriptional activity of an estrogen sensitive reporter gene. Mol. Cell. Endocrinol. 200, 199-202.
82. Hajduk, P.J., Bures, M., Praestgaard, J., and Fesik, S.W. (2000). Privileged molecules for protein binding identified from NMR-based screening. J. Med. Chem. 43, 3443-3447.
83. Aronov, A.M., and Murcko, M.A. (2004). Toward a pharmacophore for kinase frequent hitters. J. Med. Chem. 47, 5616-5619.
84. Schreiber, S.L. (1991). Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science 251, 283-287.
85. Heitman, J., Movva, N.R., and Hall, M.N. (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905-909.
86. Choi, J., Chen, J., Schreiber, S.L., and Clardy, J. (1996). Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239-242.
87. Zheng, X.F., Florentino, D., Chen, J., Crabtree, G.R., and Schreiber, S.L. (1995). TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82, 121-130.
88. Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Ruegg, M.A., Hall, A., and Hall, M.N. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122-1128.
89. Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J.L., Bonenfant, D., Oppliger, W., Jenoe, P., and Hall, M.N. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457-468.
90. Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J., and Saltiel, A.R. (1995). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA 92, 7686-7689.
91. Alessi, D.R., Cuenda, A., Cohen, P., Dudley, D.T., and Saltiel, A.R. (1995). PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489-27494.
92. Favata, M.F., Horiuchi, K.Y., Manos, E.J., Daulerio, A.J., Stradley, D.A., Feeser, W.S., Van Dyk, D.E., Pitts, W.J., Earl, R.A., Hobbs, F., et al. (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623-18632.
93. Sebolt-Leopold, J.S., Dudley, D.T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R.C., Tecle, H., Barrett, S.D., Bridges, A., Przybranowski, S., et al. (1999). Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. 5, 810-816.
94. Ohren, J.F., Chen, H., Pavlovsky, A., Whitehead, C., Zhang, E., Kuffa, P., Yan, C., McConnell, P., Spessard, C., Banotai, C., et al. (2004). Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 11, 1192-1197.
95. Davidson, W., Frego, L., Peet, G.W., Kroe, R.R., Labadia, M.E., Lukas, S.M., Snow, R.J., Jakes, S., Grygon, C.A., Pargellis, C., et al. (2004). Discovery and characterization of a substrate selective p38alpha inhibitor. Biochemistry 43, 11658-11671.
96. Martin, J.L., Avkiran, M., Quinlan, R.A., Cohen, P., and Marber, M.S. (2001). Antiischemic effects of SB203580 are mediated through the inhibition of p38alpha mitogen-activated protein kinase: evidence from ectopic expression of an inhibition-resistant kinase. Circ. Res. 89, 750-752.
97. Gorre, M.E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P.N., and Sawyers, C.L. (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876-880.
98. Bishop, A.C., Ubersax, J.A., Petsch, D.T., Matheos, D.P., Gray, N.S., Blethrow, J., Shimizu, E., Tsien, J.Z., Schultz, P.G., Rose, M.D., et al. (2000). A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407, 395-401.
99. Jackson, A.L., and Linsley, P.S. (2004). Noise amidst the silence: off-target effects of siRNAs? Trends Genet. 20, 521-524.
100. Zambrowicz, B.P., and Sands, A.T. (2003). Knockouts model the 100 best-selling drugs - will they model the next 100? Nat. Rev. Drug Discov. 2, 38-51.
101. Hardy, L.W., and Peet, N.P. (2004). The multiple orthogonal tools approach to define molecular causation in the validation of druggable targets. Drug Discov. Today 9, 117-126.
102. Chong, Y.P., Mulhern, T.D., Zhu, H.J., Fujita, D.J., Bjorge, J.D., Tantiongco, J.P., Sotirellis, N., Lio, D.S., Scholz, G., and Cheng, H.C. (2004). A novel non-catalytic mechanism employed by the C-terminal Src-homologous kinase to inhibit Src-family kinase activity. J. Biol. Chem. 279, 20752-20766.
103. Patrucco, E., Notte, A., Barberis, L., Selvetella, G., Maffei, A., Brancaccio, M., Marengo, S., Russo, G., Azzolino, O., Rybalkin, S.D., et al. (2004). PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118, 375-387.
104. Papa, F.R., Zhang, C., Shokat, K., and Walter, P. (2003). By-passing a kinase activity with an ATP-competitive drug. Science 302, 1533-1537.
105. Yu, V.P., Baskerville, C., Grunenfelder, B., and Reed, S.I. (2005). A kinase-independent function of Cks1 and Cdk1 in regulation of transcription. Mol. Cell 17, 145-151.
106. Cohen, P. (2002). Protein kinases - the major drug targets of the twenty-first century? Nat. Rev. Drug Discov. 1, 309-315.
107. Ortega, S., Prieto, I., Odajima, J., Martin, A., Dubus, P., Sotillo, R., Barbero, J.L., Malumbres, M., and Barbacid, M. (2003). Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat. Genet. 35, 25-31.
108. Lowell, C.A., Soriano, P., and Varmus, H.E. (1994). Functional overlap in the src gene family: inactivation of hck and fgr impairs natural immunity. Genes Dev. 8, 387-398.
109. Lowell, C.A., Niwa, M., Soriano, P., and Varmus, H.E. (1996). Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. Blood 87, 1780-1792.
110. Abeliovich, H., Zhang, C., Dunn, W.A., Jr., Shokat, K.M., and Klionsky, D.J. (2003). Chemical genetic analysis of Apg1 reveals a non-kinase role in the induction of autophagy. Mol. Biol. Cell 14, 477-490.
111. Weiss, E.L., Bishop, A.C., Shokat, K.M., and Drubin, D.G. (2000). Chemical genetic analysis of the budding-yeast p21-activated kinase Cla4p. Nat. Cell Biol. 2, 677-685.
112. Sreenivasan, A., Bishop, A.C., Shokat, K.M., and Kellogg, D.R. (2003). Specific inhibition of Elm1 kinase activity reveals functions required for early G1 events. Mol. Cell. Biol. 23, 6327-6337.
113. Vanhaesebroeck, B., Rohn, J.L., and Waterfield, M.D. (2004). Gene targeting: attention to detail. Cell 118, 274-276.
114. Okkenhaug, K., Bilancio, A., Farjot, G., Priddle, H., Sancho, S., Peskett, E., Pearce, W., Meek, S.E., Salpekar, A., Waterfield, M.D., et al. (2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297, 1031-1034.
115. Jou, S.T., Carpino, N., Takahashi, Y., Piekorz, R., Chao, J.R., Carpino, N., Wang, D., and Ihle, J.N. (2002). Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22, 8580-8591.
116. Wong, S., McLaughlin, J., Cheng, D., Zhang, C., Shokat, K.M., and Witte, O.N. (2004). Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations. Proc. Natl. Acad. Sci. USA 101, 17456-17461.
117. Liu, Y., Kung, C., Fishburn, J., Ansari, A.Z., Shokat, K.M., and Hahn, S. (2004). Two cyclin-dependent kinases promote RNA polymerase II transcription and formation of the scaffold complex. Mol. Cell. Biol. 24, 1721-1735.
118. Williams, M. (2003). Target validation. Curr. Opin. Pharmacol. 3, 571-577.
119. Fraley, M.E., Hoffman, W.F., Rubino, R.S., Hungate, R.W., Tebben, A.J., Rutledge, R.Z., McFall, R.C., Huckle, W.R., Kendall, R.L., Coll, K.E., et al. (2002). Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors. Bioorg. Med. Chem. Lett. 12, 2767-2770.
120. Bilodeau, M.T., Cunningham, A.M., Koester, T.J., Ciecko, P.A., Coll, K.E., Huckle, W.R., Hungate, R.W., Kendall, R.L., McFall, R.C., Mao, X., et al. (2003). Design and synthesis of 1,5-diaryl-benzimidazoles as inhibitors of the VEGF-receptor KDR. Bioorg. Med. Chem. Lett. 13, 2485-2488.
121. Fraley, M.E., Arrington, K.L., Hambaugh, S.R., Hoffman, W.F., Cunningham, A.M., Young, M.B., Hungate, R.W., Tebben, A.J., Rutledge, R.Z., Kendall, R.L., et al. (2003). Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H- indoles as a novel class of KDR kinase inhibitors. Bioorg. Med. Chem. Lett. 13, 2973-2976.
122. Manley, P.J., Balitza, A.E., Bilodeau, M.T., Coll, K.E., Hartman, G.D., McFall, R.C., Rickert, K.W., Rodman, L.D., and Thomas, K.A. (2003). 2,4-disubstituted pyrimidines: a novel class of KDR kinase inhibitors. Bioorg. Med. Chem. Lett. 13, 1673-1677.
123. Murata, T., Shimada, M., Sakakibara, S., Yoshino, T., Kadono, H., Masuda, T., Shimazaki, M., Shintani, T., Fuchikami, K., Sakai, K., et al. (2003). Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1. Bioorg. Med. Chem. Lett. 13, 913-918.
124. Murata, T., Shimada, M., Sakakibara, S., Yoshino, T., Masuda, T., Shintani, T., Sato, H., Koriyama, Y., Fukushima, K., Nunami, N., et al. (2004). Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: orally active anti-inflammatory agents. Bioorg. Med. Chem. Lett. 14, 4019-4022.
125. Baxter, A., Brough, S., Cooper, A., Floettmann, E., Foster, S., Harding, C., Kettle, J., McInally, T., Martin, C., Mobbs, M., et al. (2004). Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors. Bioorg. Med. Chem. Lett. 14, 2817-2822.
126. Burchat, A.F., Calderwood, D.J., Friedman, M.M., Hirst, G.C., Li, B., Rafferty, P., Ritter, K., and Skinner, B.S. (2002). Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck-a selectivity insight. Bioorg. Med. Chem. Lett. 12, 1687-1690.
127. Goldberg, D.R., Butz, T., Cardozo, M.G., Eckner, R.J., Hammach, A., Huang, J., Jakes, S., Kapadia, S., Kashem, M., Lukas, S., et al. (2003). Optimization of 2-phenylaminoimidazo[4,5-h]isoquinolin-9-ones: orally active inhibitors of lck kinase. J. Med. Chem. 46, 1337-1349.
128. Chen, P., Doweyko, A.M., Norris, D., Gu, H.H., Spergel, S.H., Das, J., Moquin, R.V., Lin, J., Wityak, J., Iwanowicz, E.J., et al. (2004). Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity. J. Med. Chem. 47, 4517-4529.
129. Das, J., Lin, J., Moquin, R.V., Shen, Z., Spergel, S.H., Wityak, J., Doweyko, A.M., DeFex, H.F., Fang, Q., Pang, S., et al. (2003). Molecular design, synthesis, and structure-Activity relationships leading to the potent and selective p56(lck) inhibitor BMS-243117. Bioorg. Med. Chem. Lett. 13, 2145-2149.
130. Chen, P., Norris, D., Das, J., Spergel, S.H., Wityak, J., Leith, L., Zhao, R., Chen, B.C., Pitt, S., Pang, S., et al. (2004). Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Bioorg. Med. Chem. Lett. 14, 6061-6066.