Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors

Journal of Medicinal Chemistry

Volumn 47, Issue 6, 2004, Pages 1375-1390

  Breitenlechner, Christine B ^b   Wegge, Thomas ^a   Berillon, Laurent ^a   Graul, Klaus ^a   Marzenell, Klaus ^a   Friebe, Walter Gunar ^a   Thomas, Ulrike ^a   Schumacher, Ralf ^a   Huber, Robert ^b   Engh, Richard A ^a,b   Masjost, Birgit ^a  

^a ROCHE DIAGNOSTICS GMBH   (Germany)

^b MAX PLANCK INSTITUTE OF BIOCHEMISTRY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

4 (2 FLUORO 6 HYDROXY 3 METHOXYBENZOYL)BENZOIC ACID 3 [(PYRIDINE 4 CARBONYL)AMINO]AZEPAN 4 YL ESTER; AZEPANE DERIVATIVE; CYCLIC AMP DEPENDENT PROTEIN KINASE; N [4 [2 [4 (2 FLUORO 6 HYDROXY 3 METHOXYBENZOYL)PHENYL]VINYL]AZEPAN 3 YL]ISONICOTINAMIDE; N [4 [4 (2 FLUORO 6 HYDROXY 3 METHOXYBENZOYL)BENZOYLAMINO]AZEPAN 3 YL]ISONICOTINAMIDE; N [4 [4 (2 FLUORO 6 HYDROXY 3 METHOXYBENZOYL)BENZYLAMINO]AZEPAN 3 YL]ISONICOTINAMIDE; N [4 [4 (2 FLUORO 6 HYDROXY 3 METHOXYBENZOYL)BENZYLOXY]AZEPAN 3 YL]ISONICOTINAMIDE; N [4 [[4 (2 FLUORO 6 HYDROXY 3 METHOXYBENZOYL)PHENYLAMINO]METHYL]AZEPAN 3 YL]ISONICOTINAMIDE; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING KINETICS; COMPLEX FORMATION; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BLOOD LEVEL; DRUG CONFORMATION; DRUG DESIGN; DRUG HALF LIFE; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IC 50; IN VITRO STUDY; MOLECULAR MODEL; NONHUMAN; STRUCTURE ANALYSIS;

ANIMALS; AZEPINES; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG STABILITY; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN BINDING; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 12144287555     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0310479     Document Type: Article

References (59)

1. Masjost, B. S. R.; Schumacher, R.; Friebe, W.-G. Novel azepane derivatives. PCT Int. Appl. WO03/076429 (Roche Diagnostics GmbH, Germany), 2003.
2. Cross, T. G.; Scheel-Toellner, D.; Henriquez, N. V.; Deacon, E.; Salmon, M.; Lord, J. M. Serine/threonine protein kinases and apoptosis. Exp. Cell Res. 2000, 256, 34-41.
3. Kozikowski, A. P.; Sun, H.; Brognard, J.; Dennis, P. A. Novel PI analogues selectively block activation of the pro-survival Serine/Threonine Kinase Akt. J. Am. Chem. Soc. 2003, 125, 1144-1145.
4. Vanhaesebroeck, B.; Alessi, D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 2000, 346 Pt 3, 561-576.
5. Blume-Jensen, P.; Hunter, T. Oncogenic kinase signalling. Nature 2001, 411, 355-365.
6. Kandel, E. S.; Hay, N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res. 1999, 253, 210-229.
7. Datta, S. R.; Brunet, A.; Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 1999, 13, 2905-2927.
8. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489-501.
9. Testa, J. R.; Bellacosa, A. AKT plays a central role in tumori-genesis. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 10983-10985.
10. Malik, S. N.; Brattain, M.; Ghosh, P. M.; Troyer, D. A.; Prihoda, T.; Bedolla, R.; Kreisberg, J. I. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin. Cancer Res. 2002, 8, 1168-1171.
11. Thakkar, H.; Chen, X.; Tyan, F.; Gim, S.; Robinson, H.; Lee, C.; Pandey, S. K.; Nwokorie, C.; Onwudiwe, N.; Srivastava, R. K. Pro-survival function of Akt/protein kinase B in prostate cancer cells. Relationship with TRAIL resistance. J. Biol. Chem. 2001, 276, 38361-38369.
12. Stal, O.; Perez-Tenorio, G.; Akerberg, L.; Olsson, B.; Nordenskjold, B.; Skoog, L.; Rutqvist, L. E. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 2003, 5, R37-44.
13. Nesterov, A.; Lu, X.; Johnson, M.; Miller, G. J.; Ivashchenko, Y.; Kraft, A. S. Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. J. Biol. Chem. 2001, 276, 10767-10774.
14. Paweletz, C. P.; Charboneau, L.; Bichsel, V. E.; Simone, N. L.; Chen, T. ; Gillespie, J. W.; Emmert-Buck, M. R.; Roth, M. J.; Petricoin, I. E.; Liotta, L. A. Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 2001, 20, 1981-1989.
15. Beresford, S. A.; Davies, M. A.; Gallick, G. E.; Donato, N. J. Differential effects of phosphatidylinositol-3/Akt-kinase inhibition on apoptotic sensitization to cytokines in LNCaP and PC-3 prostate cancer cells. J. Interferon Cytokine Res. 2001, 21, 313-322.
16. Kumar, C. C.; Diao, R.; Yin, Z.; Liu, Y.; Samatar, A. A.; Madison, V.; Xiao, L. Expression, purification, characterization and homology modeling of active Akt/PKB, a key enzyme involved in cell survival signaling. Biochim. Biophys. Acta 2001, 1526, 257-268.
17. Yang, J.; Cron, P.; Good, V. M.; Thompson, V.; Hemmings, B. A.; Barford, D. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat. Struct. Biol. 2002, 9, 940-944.
18. Yang, J.; Cron, P.; Thompson, V.; Good, V. M.; Hess, D.; Hemmings, B. A. ; Barford, D. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 2002, 9, 1227-1240.
19. Jirousek, M. R.; Gillig, J. R.; Gonzalez, C. M.; Heath, W. F.; McDonald, J. H., 3rd; Neel, D. A.; Rito, C. J.; Singh, U.; Stramm, L. E.; Melikian-Badalian, A.; Baevsky, M.; Ballas, L. M.; Hall, S. E.; Winneroski, L. L.; Faul, M. M. (S)-13-[(dimethylamino)-methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h] [1,4,13]oxadiazacyclohexadecene-1,3-(2H)-dione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. J. Med. Chem. 1996, 39, 2664-2671.
20. Tenzerf A.; Zingg, D.; Rocha, S.; Hemmings, B.; Fabbro, D.; Glanzmann, C.; Schubiger, P. A.; Bodis, S.; Pruschy, M. The phosphatidylinositide 3′-kinase/Akt survival pathway is a target for the anticancer and radiosensitizing agent PKC412, an inhibitor of protein kinase C. Cancer Res. 2001, 61, 8203-8210.
21. Heath, W. F., Jr.; Jirousek, M. R.; McDonald, J. H., III; Rito, C. J. Preparation of bis(indolyl)maleimide macrocycles as beta-isoenzyme selective protein kinase C inhibitors. Eur. Pat. Appl. (Lilly, Eli, and Co.) EP657458, 1995; 70 pp.
22. Caravatti, G.; Fredenhagen, A. Preparation of N-acyl- and N-hydrecarbylstaurosporines as protein kinase C inhibitors. Eur. Pat. Appl. (Ciba-Geigy A.-G., Switz.) EP296110, 1988; 27 pp.
23. Kulanthaivel, P.; Hallock, Y.; Boros, C.; Hamilton, S. M.; Janzen, W. P. ; Ballas, L. M.; Loomis, C. R.; Jiang, J. B.; Katz, J. B.; Steiner, J. R.; Clardy, J. Balanol: A Novel and Potent Inhibitor of Protein Kinase C from the Fungus Verticillium balanoides. J. Am. Chem. Soc. 1993, 115, 6452-6453.
24. Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujii, T.; Sano, T.; Matsukuma, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.; et al. Fusarium merismoides Corda NR 6356, the source of the protein kinase C inhibitor, azepinostatin. Taxonomy, yield improvement, fermentation and biological activity. J. Antibiot. (Tokyo) 1994, 47, 639-647.
25. Narayana, N.; Diller, T. C.; Koide, K.; Bunnage, M. E.; Nicolaou, K. C.; Brunton, L. L.; Xuong, N. H.; Ten Eyck, L. F.; Taylor, S. S. Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of cAMP-dependent protein kinase. Biochemistry 1999, 38, 2367-2376.
26. Hunenberger, P. H.; Helms, V.; Narayana, N.; Taylor, S. S.; McCammon, J. A. Determinants of ligand binding to cAMP-dependent protein kinase. Biochemistry 1999, 38, 2358-2366.
27. Koide, K.; Bunnage, M. E.; Gomez Paloma, L.; Kanter, J. R.; Taylor, S. S.; Brunton, L. L.; Nicolaou, K. C. Molecular design and biological activity of potent and selective protein kinase inhibitors related to balanol. Chem. Biol. 1995, 2, 601-608.
28. Gustafsson, A. B.; Brunton, L. L. Differential and selective inhibition of protein kinase A and protein kinase C in intact cells by balanol congeners. Mol. Pharmacol. 1999, 56, 377-382.
29. Lampe, J. W.; Biggers, C. K.; Defauw, J. M.; Foglesong, R. J.; Hall, S. E.; Heerding, J. M.; Hollinshead, S. P.; Hu, H.; Hughes, P. F.; Jagdmann, G. E., Jr.; Johnson, M. G.; Lai, Y. S.; Lowden, C. T.; Lynch, M. P.; Mendoza, J. S.; Murphy, M. M.; Wilson, J. W.; Ballas, L. M.; Carter, K.; Darges, J. W.; Davis, J. E.; Hubbard, F. R.; Stamper, M. L. Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits. J. Med. Chem. 2002, 45, 2624-2643.
30. Jagdmann, G. E.; Defauw, J. M.; Lampe, J. W.; Darges, J. W.; Kalter, K. Potent and selective PKC inhibitory five-membered ring analogues of balanol with replacement of the carboxamide moiety. Bioorg. Med. Chem. Lett. 1996, 6, 1759-1764.
31. Setyawan, J.; Koide, K.; Diller, T. C.; Bunnage, M. E.; Taylor, S. S.; Nicolaou, K. C.; Brunton, L. L. Inhibition of protein kinases by balanol: specificity within the serine/threonine protein kinase subfamily. Mol. Pharmacol. 1999, 56, 370-376.
32. Hall, S. E.; Ballas, L. M.; Kulanthaivel, P.; Boros, C.; Jiang, J. B.; Jagdmann, G. E., Jr.; Lai, Y.-S.; Biggers, C. K.; Hu, H.; et al. Preparation of balanoids as protein kinase C inhibitors. PCT Int. Appl. (Nichols, Gina M.; Sphinx Pharmaceuticals Corporation). WO9420062, 1994; 559 pp.
33. Hu, H.; Jagdmann, G. E., Jr.; Mendoza, J. S. Preparation of substituted fused and bridged bicyclic compound protein kinase C inhibitors. PCT Int. Appl. (Lilly, Eli, and Co.). WO9530640, 1995; 84 pp.
34. Barbier, P.; Stadlwieser, J.; Taylor, S. Novel azepanes and their ring homologs for therapy and prophylaxis of protein kinase mediated diseases. PCT Int. Appl. (F. Hoffmann-La Roche AG) WO9702249, 1997; 43 pp.
35. Barbier, P.; Huber, I.; Schneider, F.; Stadlwieser, J.; Taylor, S. Preparation of 3-amino/hydroxy-4-[4-benzoylphenylcarboxylamino/oxy]azepine and homolog protein kinase inhibitors. Eur. Pat. Appl. (F. Hoffmann-La Roche AG) EP663393, 1995; 47 pp.
36. Breitenlechner, C.; Gassel, M.; Hidaka, H.; Kinzel, V.; Huber, R.; Engh, R. A.; Bossemeyer, D. Protein Kinase A in Complex with Rho-kinase Inhibitors Y-27632, Fasudil (HA-1077), and H-1152P. Structural Basis of Selectivity. Structure 2003, 11, 1595-1607.
37. Masjost, B.; Ballmer, P.; Borroni, E.; Zürcher, G.; Winkler, F. K.; Jakob-Roetne, R.; Diederich, F. Structure-based design, synthesis, and in vitro evaluation of bi-substrate inhibitors for catechol O-methyltransferase (COMT). Chem. Eur. J. 2000, 6, 971-982.
38. Lerner, C.; Ruf, A.; Gramlich, V.; Masjost, B.; Zürcher, G.; Jakob-Roetne, R.; Borroni, E.; Diederich, F. X-ray crystal structure of a bisubstrate inhibitor bound to the enzyme catechol-O-methyltransferase: a dramatic effect of inhibitor preorganization on binding affinity. Angew. Chem., Int. Ed. 2001, 40, 4040-4042.
39. Lerner, C.; Masjost, B.; Ruf, A.; Gramlich, V.; Jakob-Roetne, R.; Zürcher, G.; Borroni, E.; Diederich, F. Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): Influence of inhibitor preorganization and linker length between the two substrate moieties on binding affinity. Org. Biomol. Chem. 2003, 1, 42-49.
40. Masjost, B. Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol O-methyltransferase (COMT). Ph.D. Dissertation; Swiss Federal Institute of Technology Zurich: Zurich, 2000.
41. 2+ adenylyl imidodiphosphate and inhibitor peptide PKI(5-24). EMBO J. 1993, 12, 849-859.
42. Engh, R. A.; Girod, A.; Kinzel, V.; Huber, R.; Bossemeyer, D. Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89. Structural implications for selectivity. J. Biol. Chem. 1996, 271, 26157-26164.
43. Prade, L.; Engh, R. A.; Girod, A.; Kinzel, V.; Huber, R.; Bossemeyer, D. Staurosporine-induced conformational changes of cAMP-dependent protein kinase catalytic subunit explain inhibitory potential. Structure (London) 1997, 5, 1627-1637.
44. Johnson, D. A.; Akamine, P.; Radzio-Andzelm, E.; Madhusudan; Taylor, S. S. Dynamics of cAMP-Dependent Protein Kinase. Chem. Rev. (Washington, D. C.) 2001, 101, 2243-2270.
45. Schneider, T. Kinetische und strukturelle Untersuchungen zur Funktion ausgewählter konservierter Aminosäurereste der katalytischen Untereinheit Ca der Proteinkinase A. Ph.D. Dissertation; Universität Bielefeld: Bielefeld, 2002.
46. Gerber, P. R.; Müller, K. MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry. J. Comput.-Aided Mol. Des. 1995, 9, 251-268.
47. Insight II user guide; Molecular Simulations Inc.: San Diego.
48. Matzinger, P. K.; Scalone, M.; Zutter, U. Process and intermediates for preparing azepines. Eur. Pat. Appl. (F. Hoffmann-La Roche AG) EP802190, 1997; 18 pp.
49. Wolfe, J. P.; Buchwald, S. L. Room-temperature catalytic amination of aryl iodides. J. Org. Chem. 1997, 62, 6066-6068.
50. Cardona, M. L.; Fernandez, M. I.; Garcia, M. B.; Pedro, J. R. Synthesis of natural polyhydroxystilbenes. Tetrahedron 1986, 42, 2725-2730.
51. Mancuso, A. J.; Huang, S.-L.; Swern, D. Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide "activated" by oxalyl chloride. J. Org. Chem. 1978, 43, 2480-2482.
52. Patel, B. A.; Kim, J.-I. I.; Bender, D. D.; Kao, L.-C.; Heck, R. F. Palladium-catalyzed three carbon chain extension reactions with acrolein acetals. A convenient synthesis of conjugated dienals. J. Org. Chem. 1981, 46, 1061-1067.
53. (a) Gassel, M.; Breitenlechner, C. B.; Rüger, P.; Jucknischke, U.; Schneider, T.; Huber, R.; Bossemeyer, D.; Engh, R. A. Mutants of Protein Kinase A that Mimic the ATP-binding Site of Protein Kinase B (AKT). J. Mol. Biol. 2003, 329, 1021-1034.
54. (b) Wegge, T.; Breitenlechner, C.; Schäfer, W.; Thomas, U.; Künkele, K.-P.; Engh, R. A.; Masjost, B., unpublished results.
55. Kraulis, P. J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 1991, 24, 945-949.
56. Esnouf, R. M. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J. Mol. Graphics Modell. 1997, 15, 132-134.
57. Esnouf, R. M. Further additions to MolScript version 1.4, including reading and contouring of electron-density maps. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1999, D55, 938-940.
58. Merritt, E. A.; Murphy, M. E. P. Raster3D version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, D50, 869-873.
59. Merritt, E. A.; Bacon, D. J. Raster3D: photorealistic molecular graphics. Methods Enzymol. 1997, 277, 505-524.