New potent dual inhibitors of CK2 and Pim kinases: Discovery and structural insights

FASEB Journal

Volumn 24, Issue 9, 2010, Pages 3171-3185

  López Ramos, Miriam ^a,b,c   Prudent, Renaud ^c,d,e   Moucadel, Virginie ^c,d,e   Sautel, Céline F ^c,d,e   Barette, Caroline ^b,f   Lafanechère, Laurence ^b,f   Mouawad, Liliane ^a,c   Grierson, David ^a,b   Schmidt, Frédéric ^a,b   Florent, Jean Claude ^a,b   Filippakopoulos, Panagis ^g   Bullock, Alex N ^g   Knapp, Stefan ^g,h   Reiser, Jean Baptiste ^i,j   Cochet, Claude ^c,d,e  

^a INSTITUT CURIE   (France)

^b CNRS   (France)

^c INSERM   (France)

^d DIF   (France)

^e UNIV GRENOBLE ALPES   (France)

^f iRTSV   (France)

^g UNIVERSITY OF OXFORD   (United Kingdom)

^h UNIVERSITY OF OXFORD   (United Kingdom)

ⁱ INSTITUT DE BIOLOGIE STRUCTURALE   (France)

^j Partnership for Structural Biology   (France)

more..

Author keywords

Binding mode; Comparative structural study; High throughput screening; Selective inhibition; X ray crystallography

Indexed keywords

2,8 DIFURANDICARBOXYLIC ACID DERIVATIVE; CASEIN KINASE II; CASEIN KINASE II INHIBITOR; ENZYME INHIBITOR; PROTEIN KINASE PIM 1; PROTEIN KINASE PIM INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION; THERMOSTABILITY;

EID: 77956631541     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.09-143743     Document Type: Article

References (88)

1. Ahmed, K., Gerber, D. A., and Cochet, C. (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol. 12, 226-230
2. Bibby, A. C., and Litchfield, D. W. (2005) The multiple personalities of the regulatory subunit of protein kinase CK2: CK2 dependent and CK2 independent roles reveal a secret identity for CK2beta. Int. J. Biol. Sci. 1, 67-79
3. Litchfield, D. W. (2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem. J. 369, 1-15
4. Meggio, F., and Pinna, L. A. (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J. 17, 349-368
5. Ahmad, K. A., Wang, G., Slaton, J., Unger, G., and Ahmed, K. (2005) Targeting CK2 for cancer therapy. Anticancer Drugs 16, 1037-1043
6. Valdman, A., Fang, X., Pang, S. T., Ekman, P., and Egevad, L. (2004) Pim-1 expression in prostatic intraepithelial neoplasia and human prostate cancer. Prostate 60, 367-371 (Pubitemid 39050657)
7. Xie, Y., Xu, K., Dai, B., Guo, Z., Jiang, T., Chen, H., and Qiu, Y. (2006) The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX and protects human prostate cancer cells from apoptosis induced by chemotherapeutic drugs. Oncogene 25, 70-78 (Pubitemid 43050005)
8. Laramas, M., Pasquier, D., Filhol, O., Ringeisen, F., Descotes, J. L., and Cochet, C. (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur. J. Cancer 43, 928-934 (Pubitemid 46366689)
9. O-charoenrat, P., Rusch, V., Talbot, S. G., Sarkaria, I., Viale, A., Socci, N., Ngai, I., Rao, P., and Singh, B. (2004) Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung. Clin. Cancer Res. 10, 5792-5803 (Pubitemid 39180957)
10. Kim, J. S., Eom, J. I., Cheong, J. W., Choi, A. J., Lee, J. K., Yang, W. I., and Min, Y. H. (2007) Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin. Cancer Res. 13, 1019-1028
11. Slaton, J. W., Unger, G. M., Sloper, D. T., Davis, A. T., and Ahmed, K. (2004) Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model. Mol. Cancer Res. 2, 712-721
12. Pagano, M. A., Cesaro, L., Meggio, F., and Pinna, L. A. (2006) Protein kinase CK2: a newcomer in the "druggable kinome." Biochem. Soc. Trans. 34, 1303-1306
13. Qian, K. C., Wang, L., Hickey, E. R., Studts, J., Barringer, K., Peng, C., Kronkaitis, A., Li, J., White, A., Mische, S., and Farmer, B. (2005) Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase. J. Biol. Chem. 280, 6130-6137 (Pubitemid 40280098)
14. Niefind, K., Guerra, B., Pinna, L. A., Issinger, O. G., and Schomburg, D. (1998) Crystal structure of the catalytic subunit of protein kinase CK2 from Zea mays at 2.1 A resolution. EMBO J. 17, 2451-2462 (Pubitemid 28221181)
15. Sarno, S., Ghisellini, P., and Pinna, L. A. (2002) Unique activation mechanism of protein kinase CK2. The N-terminal segment is essential for constitutive activity of the catalytic subunit but not of the holoenzyme. J. Biol. Chem. 277, 22509-22514
16. Raaf, J., Issinger, O. G., and Niefind, K. (2008) Insights from soft X-rays: the chlorine and sulfur sub-structures of a CK2alpha/DRB complex. Mol. Cell. Biochem. 316, 15-23
17. Cibull, T. L., Jones, T. D., Li, L., Eble, J. N., Ann Baldridge, L., Malott, S. R., Luo, Y., and Cheng, L. (2006) Overexpression of Pim-1 during progression of prostatic adenocarcinoma. J. Clin. Pathol. 59, 285-288 (Pubitemid 43344891)
18. Chen, J., Kobayashi, M., Darmanin, S., Qiao, Y., Gully, C., Zhao, R., Yeung, S. C., and Lee, M. H. (2009) Pim-1 plays a pivotal role in hypoxia-induced chemoresistance. Oncogene 28, 2581-2592
19. Yan, B., Zemskova, M., Holder, S., Chin, V., Kraft, A., Koskinen, P. J., and Lilly, M. (2003) The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J. Biol. Chem. 278, 45358-45367 (Pubitemid 37432672)
20. Duncan, J. S., and Litchfield, D. W. (2008) Too much of a good thing: The role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim. Biophys. Acta 1784, 33-47
21. Ruzzene, M., and Pinna, L. A. (2009) Addiction to protein kinase CK2: A common denominator of diverse cancer cells? Biochim. Biophys. Acta 1804, 499-504
22. Morishita, D., Katayama, R., Sekimizu, K., Tsuruo, T., and Fujita, N. (2008) Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 68, 5076-5085
23. Aho, T. L., Sandholm, J., Peltola, K. J., Ito, Y., and Koskinen, P. J. (2006) Pim-1 kinase phosphorylates RUNX family transcription factors and enhances their activity. BMC Cell Biol. 7, 21
24. Zemskova, M., Sahakian, E., Bashkirova, S., and Lilly, M. (2008) The PIM1 kinase is a critical component of a survival pathway activated by docetaxel and promotes survival of docetaxel-treated prostate cancer cells. J. Biol. Chem. 283, 20635-20644
25. Lilly, M., Sandholm, J., Cooper, J. J., Koskinen, P. J., and Kraft, A. (1999) The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway. Oncogene 18, 4022-4031
26. Romieu-Mourez, R., Landesman-Bollag, E., Seldin, D. C., Traish, A. M., Mercurio, F., and Sonenshein, G. E. (2001) Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. Cancer Res. 61, 3810-3818
27. Landesman-Bollag, E., Song, D. H., Romieu-Mourez, R., Sussman, D. J., Cardiff, R. D., Sonenshein, G. E., and Seldin, D. C. (2001) Protein kinase CK2: signaling and tumorigenesis in the mammary gland. Mol. Cell. Biochem. 227, 153-165
28. Hammerman, P. S., Fox, C. J., Cinalli, R. M., Xu, A., Wagner, J. D., Lindsten, T., and Thompson, C. B. (2004) Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation. Cancer Res. 64, 8341-8348
29. Ayala, G. E., Dai, H., Ittmann, M., Li, R., Powell, M., Frolov, A., Wheeler, T. M., Thompson, T. C., and Rowley, D. (2004) Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res. 64, 6082-6090 (Pubitemid 39129408)
30. Klumpp, S., Maurer, A., Zhu, Y., Aichele, D., Pinna, L. A., and Krieglstein, J. (2004) Protein kinase CK2 phosphorylates BAD at threonine-117. Neurochem. Int. 45, 747-752 (Pubitemid 38844897)
31. Kallergi, G., Markomanolaki, H., Giannoukaraki, V., Papadaki, M. A., Strati, A., Lianidou, E. S., Georgoulias, V., Mavroudis, D., and Agelaki, S. (2009) Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res. 11, R84
32. Mottet, D., Ruys, S. P., Demazy, C., Raes, M., and Michiels, C. (2005) Role for casein kinase 2 in the regulation of HIF-1 activity. Int. J. Cancer 117, 764-774 (Pubitemid 41598827)
33. Hubert, A., Paris, S., Piret, J. P., Ninane, N., Raes, M., and Michiels, C. (2006) Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level. J. Cell Sci. 119, 3351-3362 (Pubitemid 44405220)
34. Reiser-Erkan, C., Erkan, M., Pan, Z., Bekasi, S., Giese, N. A., Streit, S., Michalski, C. W., Friess, H., and Kleeff, J. (2008) Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma. Cancer Biol. Ther. 7, 1352-1359
35. Prudent, R., Moucadel, V., Lopez-Ramos, M., Aci, S., Laudet, B., Mouawad, L., Barette, C., Einhorn, J., Einhorn, C., Denis, J. N., Bisson, G., Schmidt, F., Roy, S., Lafanechere, L., Florent, J. C., and Cochet, C. (2008) Expanding the chemical diversity of CK2 inhibitors. Mol. Cell. Biochem. 316, 71-85
36. Cozza, G., Bortolato, A., and Moro, S. (2009) How druggable is protein kinase CK2? [E-pub ahead of print] Med. Res. Rev. doi: 10.1002/med.20164
37. Anderes, K., Siddiqui-Jain, A., Streiner, P., Chua, F., Pierre, F., Omori, M., Darjania, L., Stansfield, R., Phung, J., Bliesath, J., Ho, C., Drygin, D., O'Brien, S., and Rice, W. (2009) Discovery and characterization of CX-4945, a selective orally bioavailable small molecule inhibitor of protein kinase CK2: phase 1 initiated. Poster presentaion, American Association for Cancer Research (AACR) Annual Meeting, April 18-22, 2009, Denver, CO, USA
38. Cheney, I. W., Yan, S., Appleby, T., Walker, H., Vo, T., Yao, N., Hamatake, R., Hong, Z., and Wu, J. Z. (2007) Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase. Bioorg. Med. Chem. Lett. 17, 1679-1683
39. Debreczeni, J. E., Bullock, A. N., Atilla, G. E., Williams, D. S., Bregman, H., Knapp, S., and Meggers, E. (2006) Ruthenium half-sandwich complexes bound to protein kinase Pim-1. Angew. Chem. Int. Ed. Engl. 45, 1580-1585 (Pubitemid 44109229)
40. Pierce, A. C., Jacobs, M., and Stuver-Moody, C. (2008) Docking study yields four novel inhibitors of the protooncogene Pim-1 kinase. J. Med. Chem. 51, 1972-1975 (Pubitemid 351438879)
41. Pogacic, V., Bullock, A. N., Fedorov, O., Filippakopoulos, P., Gasser, C., Biondi, A., Meyer-Monard, S., Knapp, S., and Schwaller, J. (2007) Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity. Cancer Res. 67, 6916-6924
42. Heriche, J. K., Lebrin, F., Rabilloud, T., Leroy, D., Chambaz, E. M., and Goldberg, Y. (1997) Regulation of protein phosphatase 2A by direct interaction with casein kinase 2alpha. Science 276, 952-955
43. Gerber, D. A., Souquere-Besse, S., Puvion, F., Dubois, M. F., Bensaude, O., and Cochet, C. (2000) Heat-induced relocalization of protein kinase CK2. Implication of CK2 in the context of cellular stress. J. Biol. Chem. 275, 23919-23926
44. Prudent, R., Lopez-Ramos, M., Moucadel, V., Barette, C., Grierson, D., Mouawad, L., Florent, J. C., Lafanechere, L., Schmidt, F., and Cochet, C. (2008) Salicylaldehyde derivatives as new protein kinase CK2 inhibitors. Biochim. Biophys. Acta 1780, 1412-1420
45. Filhol, O., Cochet, C., Wedegaertner, P., Gill, G. N., and Chambaz, E. M. (1991) Coexpression of both alpha and beta subunits is required for assembly of regulated casein kinase II. Biochemistry 30, 11133-11140
46. Vedadi, M., Niesen, F. H., Allali-Hassani, A., Fedorov, O. Y., Finerty, P. J., Jr., Wasney, G. A., Yeung, R., Arrowsmith, C., Ball, L. J., Berglund, H., Hui, R., Marsden, B. D., Nordlund, P., Sundstrom, M., Weigelt, J., and Edwards, A. M. (2006) Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination. Proc. Natl. Acad. Sci. U. S. A. 103, 15835-15840
47. Ermakova, I., Boldyreff, B., Issinger, O. G., and Niefind, K. (2003) Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit. J. Mol. Biol. 330, 925-934
48. Kabsch, W. (1993) Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants. J. Appl. Cryst. 26, 795-800
49. Navaza, J. (1994) AMoRe: an automated package for molecular replacement Acta Crystallogr. A 50, 157-163
50. Collaborative Computational Project, Number 4 (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760-763
51. Emsley, P., and Cowtan, K. (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132
52. Murshudov, G. N., Vagin, A. A., and Dodson, E. J. (1997) Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D Biol. Crystallogr. 53, 240-255
53. Bullock, A. N., Debreczeni, J., Amos, A. L., Knapp, S., and Turk, B. E. (2005) Structure and substrate specificity of the Pim-1 kinase. J. Biol. Chem. 280, 41675-41682
54. Leslie, A. G. W., and Powell, H. (2007) MOSFLM, MRC Laboratory of Molecular Biology, Cambridge, UK
55. Evans, P. (2007) SCALA-Scale Together Multiple Observations of Reflections, MRC Laboratory of Molecular Biology, Cambridge, UK
56. McCoy, A. J., Grosse-Kunstleve, R. W., Storoni, L. C., and Read, R. J. (2005) Likelihood-enhanced fast translation functions. Acta Crystallogr. D Biol. Crystallogr. 61, 458-464
57. Painter, J., and Merritt, E. A. (2006) Optimal description of a protein structure in terms of multiple groups undergoing TLS motion. Acta Crystallogr. D Biol. Crystallogr. 62, 439-450
58. Rarey, M., Kramer, B., Lengauer, T., and Klebe, G. (1996) A fast flexible docking method using an incremental construction algorithm. J. Mol. Biol. 261, 470-489
59. Augustin, S., ed. (2005) FlexX, BioSolveIT, Darmstadt, Germany
60. Kuntz, I. D., Blaney, J. M., Oatley, S. J., Langridge, R., and Ferrin, T. E. (1982) A geometric approach to macromolecule-ligand interactions. J. Mol. Biol. 161, 269-288
61. Moustakas, D. T., Lang, P. T., Pegg, S., Pettersen, E., Kuntz, I. D., Brooijmans, N., and Rizzo, R. C. (2006) Development and validation of a modular, extensible docking program: DOCK 5. J. Comput. Aided Mol. Des. 20, 601-619
62. MacKerell, A., Jr., Bashford, D., Bellott, M., Dunbrack, R. L., Jr., Evanseck, J. D., Field, M. J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph-McCarthy, D., Kuchnir, L., Kuczera, K., Lau, F. T. K., Mattos, C., Michnick, S., Ngo, T., Nguyen, D. T., Prodhom, B., Reiher, III, W. E., Roux, B., Schlenkrich, M., Smith, J. C., Stote, R., Straub, J., Watanabe, M., Wiórkiewicz-Kuczera, J., Yin, D., and Karplus, M. (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586-3616
63. SYBYL. Tripos Inc., 1699 South Hanley Road, St. Louis, MO, 63144
64. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Montgomery, J. A., Jr., Vreven, T., Kudin, K. N., Burant, J. C., Millam, J. M., Iyengar, S. S., Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G. A., Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J. E., Hratchian, H. P., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Ayala, P. Y., Morokuma, K., Voth, G. A., Salvador, P., Dannenberg, J. J., Zakrzewski, V. G., Dapprich, S., Daniels, A. D., Strain, M. C., Farkas, O., Malick, D. K., Rabuck, A. D., Raghavachari, K., Foresman, J. B., Ortiz, J. V., Cui, Q., Baboul, A. G., Clifford, S., Cioslowski, J., Stefanov, B. B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R. L., Fox, D. J., Keith, T., Al-Laham, M. A., Peng, C. Y., Nanayakkara, A., Challacombe, M., Gill, P. M. W., Johnson, B., Chen, W., Wong, M. W., Gonzalez, C., and Pople, J. A. (2004) Gaussian 03W, Gaussian, Inc., Wallingford, CT, USA
65. Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., and Case, D. A. (2004) Development and testing of a general amber force field. J. Comput. Chem. 25, 1157-1174
66. Arrault, A., Touzeau, F., Guillaumet, G., and Mèrour, J. Y. (1999) A straightforward synthesis of 1,2-dihydronaphtho[2,1-d]furans from 2-naphthols. Synthesis 7, 1241-1245
67. Bilger, C., Demerseman, P., Buisson, J.-P., Royer, R., Gayral, P., and Fourniat, J. (1987) Sur quelques modifications d'activitébiologique consécutives à l'accolement d'un second cycle nitrofuranne à l'homocycle de nitroarenofurannes. Eur. J. Med. Chem. 22, 213-219
68. Seidler, J., McGovern, S. L., Doman, T. N., and Shoichet, B. K. (2003) Identification and prediction of promiscuous aggregating inhibitors among known drugs. J. Med. Chem. 46, 4477-4486
69. McGovern, S. L., Caselli, E., Grigorieff, N., and Shoichet, B. K. (2002) A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J. Med. Chem. 45, 1712-1722
70. Feng, B. Y., Simeonov, A., Jadhav, A., Babaoglu, K., Inglese, J., Shoichet, B. K., and Austin, C. P. (2007) A high-throughput screen for aggregation-based inhibition in a large compound library. J. Med. Chem. 50, 2385-2390
71. Shoichet, B. K. (2006) Interpreting steep dose-response curves in early inhibitor discovery. J. Med. Chem. 49, 7274-7277
72. Ryan, A. J., Gray, N. M., Lowe, P. N., and Chung, C. W. (2003) Effect of detergent on "promiscuous" inhibitors. J. Med. Chem. 46, 3448-3451
73. Pagano, M. A., Bain, J., Kazimierczuk, Z., Sarno, S., Ruzzene, M., Di Maira, G., Elliott, M., Orzeszko, A., Cozza, G., Meggio, F., and Pinna, L. A. (2008) The selectivity of inhibitors of protein kinase CK2: an update. Biochem. J. 415, 353-365
74. Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002) The protein kinase complement of human genome. Sceince 298, 1912-1934
75. Battistutta, R., De Moliner, E., Sarno, S., Zanotti, G., and Pinna, L. A. (2001) Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole. Protein. Sci. 10, 2200-2206
76. Battistutta, R., Mazzorana, M., Sarno, S., Kazimierczuk, Z., Zanotti, G., and Pinna, L. A. (2005) Inspecting the structure-activity relationship of protein kinase CK2 inhibitors derived from tetrabromo-benzimidazole. Chem. Biol. 12, 1211-1219
77. Battistutta, R., Sarno, S., De Moliner, E., Papinutto, E., Zanotti, G., and Pinna, L. A. (2000) The replacement of ATP by the competitive inhibitor emodin induces conformational modifications in the catalytic site of protein kinase CK2. J. Biol. Chem. 275, 29618-29622
78. Niefind, K., Guerra, B., Ermakowa, I., and Issinger, O. G. (2001) Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme. EMBO J. 20, 5320-5331
79. Battistutta, R. (2009) Protein kinase CK2 in health and disease: Structural bases of protein kinase CK2 inhibition. Cell. Mol. Life Sci. 66, 1868-1889
80. Niefind, K., Raaf, J., and Issinger, O. G. (2009) Protein kinase CK2 in health and disease: Protein kinase CK2: from structures to insights. Cell. Mol. Life Sci. 66, 1800-1816
81. Niefind, K., Yde, C. W., Ermakova, I., and Issinger, O. G. (2007) Evolved to be active: sulfate ions define substrate recognition sites of CK2alpha and emphasise its exceptional role within the CMGC family of eukaryotic protein kinases. J. Mol. Biol. 370, 427-438
82. Raaf, J., Brunstein, E., Issinger, O. G., and Niefind, K. (2008) The CK2 alpha/CK2 beta interface of human protein kinase CK2 harbors a binding pocket for small molecules. Chem. Biol. 15, 111-117
83. Liao, J. J. (2007) Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem. 50, 409-424
84. Xu, Y., Zhang, T., Tang, H., Zhang, S., Liu, M., Ren, D., and Niu, Y. (2005) Overexpression of PIM-1 is a potential biomarker in prostate carcinoma. J. Surg. Oncol. 92, 326-330
85. Mazzorana, M., Pinna, L. A., and Battistutta, R. (2008) A structural insight into CK2 inhibition. Mol. Cell. Biochem. 316, 57-62
86. Sarno, S., Ruzzene, M., Frascella, P., Pagano, M. A., Meggio, F., Zambon, A., Mazzorana, M., Di Maira, G., Lucchini, V., and Pinna, L. A. (2005) Development and exploitation of CK2 inhibitors. Mol. Cell. Biochem. 274, 69-76
87. Azam, M., Powers, J. T., Einhorn, W., Huang, W. S., Shakespeare, W. C., Zhu, X., Dalgarno, D., Clackson, T., Sawyer, T. K., and Daley, G. Q. AP24163 inhibits the gatekeeper mutant of BCR-ABL and suppresses in vitro resistance. Chem. Biol. Drug Des. 75, 223-227
88. Azam, M., Seeliger, M. A., Gray, N. S., Kuriyan, J., and Daley, G. Q. (2008) Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat. Struct. Mol. Biol. 15, 1109-1118