Heteroaryl-linked 5-(1H-benzimidazol-1-yl)-2-thiophenecarboxamides: Potent inhibitors of polo-like kinase 1 (PLK1) with improved drug-like properties

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 15, 2010, Pages 4587-4592

  Rheault, Tara R ^a   Donaldson, Kelly H ^a   Badiang Alberti, Jennifer G ^a   Davis Ward, Ronda G ^a   Andrews, C Webb ^a   Bambal, Ramesh ^a   Jackson, Jeffrey R ^a   Cheung, Mui ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

CYP450 inhibition; Kinase inhibitor; Mouse iv clearance; PLK1; Polo like kinase; Solubility

Indexed keywords

CYTOCHROME P450; MYOTONIC DYSTROPHY PROTEIN KINASE; POLO LIKE KINASE 1; PROTEIN SERINE THREONINE KINASE INHIBITOR;

ARTICLE; ENZYME INHIBITION; MOUSE; NONHUMAN; SOLUBILITY; STRUCTURE ACTIVITY RELATION;

AMIDES; ANIMALS; ANTINEOPLASTIC AGENTS; BINDING SITES; CELL CYCLE PROTEINS; CELL LINE, TUMOR; COMPUTER SIMULATION; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; INJECTIONS, INTRAVENOUS; MICE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 77955422957     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.06.009     Document Type: Article

References (30)

1. L. Pecorino Molecular Biology of Cancer 2006 Oxford New York pp 1-19
2. B.A. Chabner, D.P. Ryan, L. Paz-Ares, R. Garcia-Carbonero, and P. Calabresi J.G. Hardman, L.E. Limbird, A.G. Gilman, Goodman & Gilman's the Pharmacological Basis of Therapeutics 10th ed. 2001 McGraw-Hill New York 1417 1425
3. F.A. Barr, H.H.W. Sillje, and E.A. Nigg Nat. Rev. Mol. Cell Biol. 5 2004 429
4. R.A.H. Fisher, and D.K. Ferris Curr. Med. Chem. Immune, Endocr. & Metabol. Agents 2 2002 125
5. D.M. Glover, I.M. Hagan, and A.A.M. Tavares Genes Dev. 12 1998 3777
6. K.E. Mundt, R.M. Golsteyn, H.A. Lane, and E.A. Nigg Biochem. Biophys. Res. Commun. 239 1997 377
7. The PLK family also includes PLK2 (SNK), PLK3 (PRK/FNK), and PLK4 (SAK), although it is unknown whether selectivity versus these family members is either desirable or necessary for an anticancer treatment S. Ma, J. Charron, and R.L. Erikson Mol. Cell. Biol. 19 2003 6936
8. B. Ouyang Et al. Jopurnal Biol. Chem. 272 1997 28646
9. C. Fode, B. Motro, S. Yousefi, M. Heffernan, and J.W. Dennis Proc. Natl Acad. Sci. USA 91 1994 6388
10. X. Liu, and R.L. Erikson Proc. Natl. Acad. Sci. USA 100 2003 5789
11. H. Yim, and R.L. Erikson Mol. Cell. Biol. 29 2009 2609
12. B. Spänkuch, E. Kurunci-Csacsko, M. Kaufmann, and K. Strebhardt Oncogene 26 2007 5793
13. R. Lez, A. Piper, B. Kronenberger, M. Kock, M. Brendel, E. Hermann, U. Pliquett, E. Neumann, and S. Zeuzem Oncogene 22 2003 69
14. X. Liu, M. Lei, and R.L. Erikson Mol. Cell. Biol. 26 2006 2093
15. N. Takai, R. Hamanaka, J. Yoshimatsu, and I. Miyakawa Oncogene 24 2005 287
16. S. Kanaji, H. Saito, and S. Tsujitani Oncology 2006 126
17. W. Weichert, G. Kristiansen, and M. Schmidt World J. Gastroenterol. 11 2005 5644
18. S. Yamada, M. Ohira, and H. Horie Oncogene 23 2004 5901
19. K. Strebhardt, and A. Ullrich Nat. Rev. Cancer 6 2006 321
20. E.K. Rowinsky, and A.W. Tolcher Pharmacology of Cancer Chemotherapy: Antimicrotubule Agents V.T. DeVita, S. Hellman, S.A. Rosenberg, Cancer: Principles & Practice of Oncology 2005 Lippincott Williams & Wilkins Philadelphia (PA) 390 416
21. K.A. Emmitte, C.W. Andrews, J.G. Badiang, R.G. Davis-Ward, H.D. Dickson, D.H. Drewry, H.K. Emerson, D.F. Hassler, V.B. Knick, K.W. Kuntz, T.J. Lansing, J.A. Linn, R.A. Mook Jr., K.E. Nailor, J.M. Salovich, G.M. Spehar, and M. Cheung Bioorg. Med. Chem. Lett. 19 2009 1018
22. K.A. Emmitte, G.M. Adjabeng, C.W. Andrews, J.G. Badiang, R. Bambal, S.D. Chamberlain, R.G. Davis-Ward, H.D. Dickson, D.F. Hassler, K.R. Hornberger, J.R. Jackson, K.W. Kuntz, T.J. Lansing, R.A. Mook Jr., K.E. Nailor, M.A. Pobanz, S.C. Smith, C.-M. Sung, and M. Cheung Bioorg. Med. Chem. Lett. 19 2009 1694
23. K.H. Hornberger, J.G. Badiang, J.M. Salovich, K.W. Kuntz, K.A. Emmitte, and M. Cheung Tetrahedron Lett. 49 2008 6348
24. T.R. Rheault, K.H. Donaldson, and M. Cheung Tetrahedron Lett. 50 2009 1399
25. The PLK1 enzyme assay was conducted using the kinase domain only. The PLK3 assay was conducted using full length enzyme. Both were in an SPA format. For a more detailed description see: T.J. Lansing, R.T. McConnell, D.R. Duckett, G.M. Spehar, V.B. Knick, D.F. Hassler, N. Noro, M. Furuta, K.A. Emmitte, T.M. Gilmer, R.A. Mook Jr., and M. Cheung Mol. Cancer Ther. 6 2007 450
26. 50 values were determined from using a 4-parameter curve fit software package (XLfit4). For a description of the MEB assay see: D.W. Rusnak, K. Lackey, K. Affleck, E.R. Wood, K.J. Alligood, N. Rhodes, B.R. Keith, D.M. Murray, W.B. Knight, R.J. Mullin, and T.M. Gilmer Mol. Cancer Ther. 1 2001 85 94
27. The inhibition of P450 activity was assessed using fluorescent probe substrates in a 96-well plate based assay format. The Gentest P450 assay format is described in the following reference: C.L. Crespi, V.P. Miller, and B.W. Penman Anal. Biochem. 248 1997 188 190 The Cypex assay format: Incubations with recombinant enzyme (Cypex Bactosomes) and test compound were performed in black 96-well clear bottom microtiter plates with a final volume of 250 μL at approximately 37 °C. Each incubation contained 220 μL of incubation mix (containing 50 mM potassium phosphate buffer pH 7.4, recombinant enzyme, and probe substrate) and 5 μL of test compound solution. Incubations for each isoform were performed separately. Samples were pre-warmed at 37 °C for 10 min before the reactions were initiated with 25 μL of an NADPH regenerating system (containing 1.7 mg NADP, 7.8 mg glucose-6-phosphate, and 6 units of glucose-6-phosphate dehydrogenase per mL). Final incubation concentrations of test compound were 0.033, 0.1, 0.33, 1, 3.3, 10, and 33 μM. Miconazole was used as positive control. Enzyme activity in the presence of test compound was normalized for the enzyme activity in absence of test compound and expressed as percent control activity. Control incubations with no inhibitor were prepared by adding 5 μL of vehicle solvent (DMSO) in place of the inhibitor. Incubations were analyzed using a fluorescence plate reader
28. The PLK1 homology model was based on the active confirmation of the protein PKA C-alpha.
29. For detailed synthetic procedures, see: Rheault, T. R.; Cheung, M.; Badiang, J. G. S.; Donaldson, K. H. PCT Int. Appl. 2008, WO 2008070354.
30. Cheung, M.; Badiang, J. G.; Donaldson, K. H.; Rheault, T. R. PCT Int. Appl. 2007, WO 2007030359.