1-substituted (dibenzo[ b,d ]thiophen-4-yl)-2-morpholino-4 h -chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity

Journal of Medicinal Chemistry

Volumn 56, Issue 16, 2013, Pages 6386-6401

  Cano, Céline ^a   Saravanan, Kappusamy ^a   Bailey, Chris ^b   Bardos, Julia ^b   Curtin, Nicola J ^c   Frigerio, Mark ^b   Golding, Bernard T ^a   Hardcastle, Ian R ^a   Hummersone, Marc G ^b   Menear, Keith A ^b   Newell, David R ^c   Richardson, Caroline J ^b   Shea, K ^b,d   Smith, Graeme C M ^b,d   Thommes, Pia ^b,d   Ting, Attilla ^d   Griffin, Roger J ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b KuDOS Pharmaceuticals Ltd   (United Kingdom)

^c NEWCASTLE UNIVERSITY   (United Kingdom)

^d ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 HYDROXYETHYLAMINO) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 (4 ETHYLPIPERAZIN 1 YL) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 (4 METHOXYBENZYLAMINO) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 (4 METHYL 1,4 DIAZEPAN 1 YL) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 (4 METHYLPIPERAZIN 1 YL) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 (AZEPAN 1 YL) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 (DIETHYLAMINO) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 [(2 (DIMETHYLAMINO)ETHYL](METHYL)AMINO) N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL]ACETAMIDE; 2 [BIS(2 METHOXYETHYL)AMINO] N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL)ACETAMIDE; 2 AMINO N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL]ACETAMIDE; 2 MORPHOLINO N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL]ACETAMIDE; AMINE; ATM PROTEIN; ATR PROTEIN; CHROMONE DERIVATIVE; CYTOTOXIC AGENT; DIBENZOTHIOPHENE DERIVATIVE; DNA DEPENDENT PROTEIN KINASE; HISTONE H2AX; MAMMALIAN TARGET OF RAPAMYCIN; MORPHOLINE DERIVATIVE; N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL] 2 (2 MORPHOLINOETHYLAMINO) 2 [(TETRAHYDROFURAN 2 YL)METHYLAMINO]ACETAMIDE; N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL] 2 (2 MORPHOLINOETHYLAMINO) 2 [2 (PIPERIDIN 1 YL)ETHYLAMINO]ACETAMIDE; N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL] 2 (2 MORPHOLINOETHYLAMINO)ACETAMIDE; N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL] 2 (PIPERAZIN 1 YL)ACETAMIDE; N [4 (2 MORPHOLINO 4 OXO 4H CHROMEN 8 YL)DIBENZO[B,D]THIOPHEN 1 YL] 2 (PIPERIDIN 1 YL)ACETAMIDE; NU 7441; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; AUTOPHOSPHORYLATION; CELL SURVIVAL; CONTROLLED STUDY; CYTOTOXICITY; DNA DAMAGE; DNA REPAIR; DRUG ACTIVITY; DRUG BINDING SITE; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; HELA CELL; IC 50; IONIZING RADIATION; PHYSICAL CHEMISTRY; SOLID PHASE SYNTHESIS; STRUCTURAL HOMOLOGY;

DNA-ACTIVATED PROTEIN KINASE; HELA CELLS; HUMANS; MORPHOLINES; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS;

EID: 84883203492     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400915j     Document Type: Article

References (35)

1. Jackson, S. P.; Bartek, J. The DNA-damage response in human biology and disease Nature 2009, 461, 1071-1078
2. Khanna, K. K.; Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection Nat. Genet. 2001, 27, 247-254
3. Collis, S. P.; DeWeese, T. L.; Jeggo, P. A.; Parker, A. R. The life and death of DNA-PK Oncogene 2005, 24, 949-961
4. Smith, G. C. M.; Jackson, S. P. Handbook of Cell Signaling; Elsevier Academic Press: New York, 2003; Vol. 1, pp 557-561.
5. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity Nat. Rev. Cancer 2003, 3, 155-168
6. Shiloh, Y. The ATM-mediated DNA-damage response: taking shape Trends Biochem. Sci. 2006, 31, 402-410
7. Helleday, T.; Petermann, E.; Lundin, C.; Hodgson, B.; Sharma, R. A. DNA repair pathways as targets for cancer threapy Nat. Rev. Cancer 2008, 8, 193-204
8. Finlay, M. R. V.; Griffin, R. J. Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family Bioorg. Med. Chem. Lett. 2012, 5352-5359
9. Curtin, N. J. DNA repair dysregulation from cancer driver to therapeutic target Nat. Rev. Cancer 2012, 12, 801-817
10. Fong, P. C.; Boss, D. S.; Yap, T. A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O'Connor, M. J.; Ashworth, A.; Carmichael, J.; Kaye, S. B.; Schellens, J. H.; de Bono, J. S. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers N. Engl. J. Med. 2009, 361, 123-134
11. Smith, G. C. M.; Jackson, S. P. The DNA-dependent protein kinase Genes Dev. 1999, 13, 916-934
12. Hill, R.; Lee, P. W. K. The DNA-dependent protein kinase (DNA-PK) Cell Cycle 2010, 9, 3460-3469
13. Jeggo, P. A.; Caldecott, K.; Pidsley, S.; Banks, G. R. Sensitivity of Chinese hamster ovary mutants defective in DNA repair to topoisomerase II inhibitors Cancer Res. 1989, 49, 7057-7063
14. Lees-Miller, S. P.; Godbout, R.; Chan, D. W.; Weinfeld, M.; Day, R. S.; Barron, G. M.; Allalunis-Turner, J. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line Science 1995, 267, 1183-1185
15. Shen, H.; Schultz, M.; Kruh, G. D.; Tew, K. D. Increased expression of the DNA-dependent protein kinase confers resistance to adriamycin Biochem. Biophys. Acta 1998, 1381, 131-138
16. Eriksson, Å.; Lewensohn, R.; Larsson, R.; Nilsson, A. DNA-dependent protein kinase in leukaemia cells and correlation with drug sensitivity Anticancer Res. 2002, 22, 1787-1794
17. Price, B. D.; Youmell, M. B. The phosphatidylinositol 3-kinase inhibitor wortmannin sensitizes murine fibroblasts and human tumor cells to radiation and blocks induction of p53 following DNA damage Cancer Res. 1995, 56, 246-250
18. Rosenzweig, K. E.; Youmell, M. B.; Palayoor, S. T.; Price, B. D. Radiosensitization of human tumor cells by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay Clin. Cancer Res. 1997, 3, 1149-1156
19. Shinohara, E. T.; Geng, L.; Tan, J.; Chen, H.; Shir, Y.; Edwards, E.; Hallbrook, J.; Kesicki, E. A.; Kashishian, A.; Hallahan, D. E. DNA dependent protein kinase (DNA-PK) is a molecular target for the development of noncytotoxic radiation-sensitizing drugs Cancer Res. 2005, 65, 4987-4992
20. Veuger, S. J.; Curtin, N. J.; Richardson, C. J.; Smith, G. C. M.; Durkacz, B. W. Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1 Cancer Res. 2003, 603, 6008-6015
21. Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4 H -1-benzopyran-4-one (LY294002) J. Biol. Chem. 1994, 269, 5241-5248
22. Izzard, R. A.; Jackson, S. P.; Smith, G. C. M. Competitive and noncompetitive inhibition of the DNA-dependent protein kinase Cancer Res. 1999, 59, 2581-2586
23. Griffin, R. J.; Fontana, G.; Golding, B. T.; Guiard, S.; Hardcastle, I. R.; Leahy, J. J. J.; Martin, N.; Richardson, C.; Rigoreau, L.; Stockley, M. L.; Smith, G. C. M. Selective benzopyranone and pyrimido[2,1- a ]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: Synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro J. Med. Chem. 2005, 48, 569-585
24. Hardcastle, I. R.; Cockcroft, X.; Curtin, N. J.; El-Murr, M. D.; Leahy, J. J. J.; Stockley, M.; Golding, B. T.; Rigoreau, L.; Richardson, C.; Smith, G. C. M.; Griffin, R. J. Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach J. Med. Chem. 2005, 48, 7829-7846
25. Hollick, J. J.; Rigoreau, L. J. M.; Cano-Soumillac, C.; Cockcroft, X.; Curtin, N. J.; Frigerio, M.; Golding, B. T.; Guiard, S.; Hardcastle, I. R.; Hickson, I.; Hummersone, M.; Menear, K. A.; Martin, N. M. B.; Matthews, I.; Newell, D. R.; Ord, R.; Richardson, C.; Smith, G. C. M.; Griffin, R. J. Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase J. Med. Chem. 2007, 50, 1958-1972
26. Desage-El Murr, M.; Cano, C.; Golding, B. T.; Hardcastle, I. R.; Hummersome, M.; Frigerio, M.; Curtin, N. J; Menear, Keith; Richardson, C.; Smith, G. C. M.; Griffin, R. J. 8-Biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) Bioorg. Med. Chem. Lett. 2008, 18, 4885-4890
27. Abbott, B.; Thompson, P. Synthetic studies of the phosphatidylinositol 3-kinase inhibitor LY294002 and related analogues Aust. J. Chem. 2003, 56, 1099-1106
28. Zhao, Y.; Thomas, H. D.; Batey, M. A.; Cowell, I. G.; Richardson, C. J.; Griffin, R. J.; Calvert, A. H.; Newell, D. R.; Smith, G. C. M.; Curtin, N. J. Preclinical evaluation of a potent novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7441 Cancer Res. 2006, 66, 5354-5362
29. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine Mol. Cell 2000, 6, 909-919
30. Kemp, D. S.; Galakatos, N. G. Peptide synthesis by prior thiol capture. 1. A convenient synthesis of 4-hydroxy-6-mercaptodibenzofuran and novel solid-phase synthesis of peptide-derived 4-(acyloxy)-6-mercaptodibenzofurans J. Org. Chem. 1986, 51, 1821-1829
31. Cano, C.; Barbeau, O. R.; Bailey, C.; Cockcroft, X.-L.; Curtin, N. J.; Duggan, H.; Frigerio, M.; Golding, B. T.; Hardcastle, I. R.; Hummersone, M. G.; Knights, C.; Menear, K. A.; Newell, D. R.; Richardson, C. J.; Smith, G. C. M.; Spittle B. Griffin, R. J. DNA-dependent protein kinase (DNA-PK) inhibitors; synthesis and biological activity of quinolin-4-one and pyridopyrimidin-4-one surrogates for the chromen-4-one chemotype J. Med. Chem. 2010, 53, 8498-8507
32. Mitchell, J.; Smith, G. C. M.; Curtin, N. J. Poly(ADP-ribose) polymerase-1 and DNA-dependent protein kinase have equivalent roles in double strand break repair following ionising radiation Int J. Radiat. Oncol. Biol. Phys. 2009, 75, 1520-1527
33. Tsuchida, R.; Yamada, T.; Takagi, M.; Shimada, A.; Ishioka, C.; Katsuki, Y.; Igarashi, T.; Chessa, L.; Delia, D.; Teraoka, H.; Mizutani, S. Detection of ATM gene mutation in human glioma cell line MO59J by a rapid frameshift/stop codon assay in yeast Radiat. Res. 2002, 158, 195-201
34. Workman, P.; Clarke, P. A.; Raynaud, F. I.; van Montfort, R. L. M. Drugging the PI3 kinome: from chemical tools to drugs in the clinic Cancer Res. 2010, 70, 2146-2157
35. Munck, J. M.; Batey, M. A.; Zhao, Y.; Jenkins, H.; Richardson, C. J.; Cano, C.; Tavecchio, M.; Barbeau, J.; Bardos, J.; Griffin, R. J.; Menear, K.; Slade, A.; Thommes, P.; Martin, N. M. B.; Newell, D. R.; Smith, G. C. M.; Curtin, N. J. Chemosensitisation of cancer cells by KU-0060648; a dual inhibitor of DNA-PK and PI-3K Mol. Can. Ther. 2012, 11, 1789-1798