Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing

Journal of Medicinal Chemistry

Volumn 54, Issue 24, 2011, Pages 8328-8342

  Reader, John C ^c   Matthews, Thomas P ^a   Klair, Suki ^c   Cheung, Kwai Ming J ^a   Scanlon, Jane ^c   Proisy, Nicolas ^a   Addison, Glynn ^c   Ellard, John ^c   Piton, Nelly ^c   Taylor, Suzanne ^c   Cherry, Michael ^c   Fisher, Martin ^c   Boxall, Kathy ^a   Burns, Samantha ^a   Walton, Michael I ^a   Westwood, Isaac M ^a,b   Hayes, Angela ^a   Eve, Paul ^a   Valenti, Melanie ^a   De Haven Brandon, Alexis ^a   Box, Gary ^a   Van Montfort, Rob L M ^a,b   Williams, David H ^c   Aherne, G Wynne ^a   Raynaud, Florence I ^a   Eccles, Suzanne A ^a   Garrett, Michelle D ^a   Collins, Ian ^a   more..

^a IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

^b INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^c Sareum Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GEMCITABINE; IRINOTECAN; PROTEIN SERINE THREONINE KINASE INHIBITOR; SAR 020106; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COLON CARCINOMA; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; MOUSE; NONHUMAN; TUMOR XENOGRAFT;

ADENOSINE TRIPHOSPHATE; ANIMALS; ANTINEOPLASTIC AGENTS; BINDING SITES; BIOLOGICAL AVAILABILITY; CELL LINE, TUMOR; CRYSTALLOGRAPHY, X-RAY; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; ISOQUINOLINES; MICE; MICE, NUDE; MOLECULAR CONFORMATION; NEOPLASM TRANSPLANTATION; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; PYRAZINES; PYRIDINES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS;

EID: 84055221857     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2007326     Document Type: Article

References (61)

1. Collins, I.; Garrett, M. D. Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. Curr. Opin. Pharmacol. 2005, 5, 366-373.
2. Dai, Y.; Grant, S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin. Cancer Res. 2010, 16, 376-383.
3. Kastan, M. B.; Bartek, J. Cell-cycle checkpoints and cancer. Nature 2004, 432, 316-323.
4. Guo, Z.; Kumagai, A.; Wang, S. X.; Dunphy, W. G. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev. 2000, 14, 2745-2756.
5. Zhao, H.; Piwnica-Worms, H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol. Cell. Biol. 2001, 21, 4129-4139.
6. Clarke, C. A.; Clarke, P. R. DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system. Biochem. J. 2005, 388, 705-712.
7. Smits, V. A. J. Spreading the signal. Dissociation of Chk1 from chromatin. Cell Cycle 2006, 5, 1039-1043.
8. Zhou, B. B.; Elledge, S. J. The DNA damage response: Putting checkpoints in perspective. Nature 2000, 408, 433-439.
9. Feijoo, C.; Hall-Jackson, C.; Wu, R.; Jenkins, D.; Leitch, J.; Gilbert, D. M.; Smythe, C. Activation of mammalian Chk1 during DNA replication arrest: A role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J. Cell Biol. 2001, 154, 913-923.
10. Peng, C. Y.; Graves, P. R.; Thoma, R. S.; Wu, Z.; Shaw, A. S.; Piwnica-Worms, H. Mitotic and G2 checkpoint control: Regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 1997, 277, 1501-1505.
11. Sanchez, Y.; Wong, C.; Thoma, R. S.; Richman, R.; Wu, Z.; Piwnica-Worms, H.; Elledge, S. J. Conservation of the Chk1 checkpoint pathway in mammals: Linkage of DNA damage to Cdk regulation through cdc25. Science 1997, 277, 1497-1501.
12. Xiao, Z.; Chen, Z.; Gunasekera, A. H.; Sowin, T. J.; Rosenberg, S. H.; Fesik, S.; Zhang, H. Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J. Biol. Chem. 2003, 278, 21767-21773.
13. Hollstein, M.; Sidransky, D.; Vogelstein, B.; Harris, C. C. p53 mutations in human cancers. Science 1991, 253, 49-53.
14. Oren, M. Regulation of the p53 tumor suppressor protein. J. Biol. Chem. 1999, 274, 36031-36034.
15. Bucher, N.; Britten, C. D. G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Br. J. Cancer 2008, 98, 523-528.
16. Kawabe, T. G2 checkpoint abrogators as anticancer drugs. Mol. Cancer Ther. 2004, 3, 513-519.
17. Walton, M. I.; Eve, P. D.; Hayes, A.; Valenti, M.; De Haven Brandon, A.; Box, G.; Boxall, K. J.; Aherne, G. W.; Eccles, S. A.; Raynaud, F. I.; Williams, D. H.; Reader, J. C.; Collins, I.; Garrett, M. D. The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106. Mol. Cancer Ther. 2010, 9, 89-100.
18. Blasina, A.; Hallin, J.; Chen, E.; Arango, M. E.; Kraynov, E.; Register, J.; Grant, S.; Ninkovic, S.; Chen, P.; Nichols, T.; O'Connor, P.; Anderes, K. Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol. Cancer Ther. 2008, 7, 2394-2404.
19. Ganzinelli, M.; Carrassa, L.; Crippa, F.; Tavecchio, M.; Broggini, M.; Damia, G. Checkpoint kinase 1 down-regulation by an inducible small interfering RNA expression system sensitized in vivo tumors to treatment with 5-fluorouracil. Clin. Cancer Res. 2008, 14, 5131-5141.
20. Tse, A. N.; Rendahl, K. G.; Sheikh, T.; Cheema, H.; Aardalen, K.; Embry, M.; Ma, S.; Moler, E. J.; Ni, Z. J.; Lopes de Menezes, D. E.; Hibner, B.; Gesner, T. G.; Schwartz, G. K. CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo. Clin. Cancer Res. 2007, 13, 591-602.
21. Xiao, Z.; Xue, J.; Sowin, T. J.; Zhang, H. Differential roles of checkpoint kinase 1, checkpoint kinase 2, and mitogen-activated protein kinase-activated protein kinase 2 in mediating DNA damage-induced cell cycle arrest: implications for cancer therapy. Mol. Cancer Ther. 2006, 5, 1935-1943.
22. Zabludoff, S. D.; Deng, C.; Grondine, M. R; Sheehy, A M.; Ashwell, S.; Caleb, B. L.; Green, S.; Haye, H. R.; Horn, C. L.; Janetka, J. W.; Liu, D.; Mouchet, E.; Ready, S.; Rosenthal, J. L.; Queva, C.; Schwartz, G. K.; Taylor, K J.; Tse, A N.; Walker, G. E.; White, A M. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNAtargeted therapies. Mol. Cancer Ther. 2008, 7, 2955-2966.
23. Garrett, M. D.; Collins, I. Anticancer therapy with checkpoint inhibitors: What, where and when? Trends Pharmacol. Sci. 2011, 32, 308-316.
24. Janetka, J. W.; Ahwell, S. Checkpoint kinase inhibitors: A review of the patent literature. Expert Opin. Ther. Pat. 2009, 19, 165-197.
25. Janetka, J. W.; Ashwell, S.; Zabludoff, S.; Lyne, P. Inhibitors of checkpoint kinases: From discovery to the clinic. Curr. Opin. Drug Discovery Dev. 2007, 10, 473-486.
26. Prudhomme, M. Novel checkpoint 1 inhibitors. Recent Pat. Anti-Cancer Drug Discovery 2006, 55-68.
27. Tao, Z.-F.; Wang, L.; Stewart, K. D.; Chen, Z.; Gu, W.; Bui, M.H.; Merta, P.; Zhang, H.; Kovar, P.; Johnson, E.; Park, C.; Judge, R; Rosenberg, S.; Sowin, T.; Lin, N.-H. Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. J. Med. Chem. 2007, 50, 1514-1527.
28. Chen, P.; Luo, C.; Deng, Y.; Ryan, K.; Register, J.; Margosiak, S.; Tempczyk-Russell, A.; Nguyen, B.; Myers, P.; Lundgren, K.; Kan, C. C.; O'Connor, P. M. The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation. Cell 2000, 100, 681-692.
29. Foloppe, N.; Fisher, L. M.; Francis, G.; Howes, R; Kierstan, P.; Potter, A Identification of a buried pocket for potent and selective inhibition of Chk1: Prediction and verification. Bioorg. Med. Chem. 2006, 14, 1792-1804.
30. Foloppe, N.; Fisher, L. M.; Howes, R; Kierstan, P.; Potter, A.; Robertson, A. G.; Surgenor, A E. Structure-based design of novel Chk1 inhibitors: Insights into hydrogen bonding and protein-ligand affinity. J. Med. Chem. 2005, 48, 4332-4345.
31. Converso, A.; Hartingh, T.; Garbaccio, R M.; Tasber, E.; Rickert, K.; Fraley, M. E; Yan, Y.; Kreatsoulas, C.; Stirdivant, S.; Drakas, B.; Walsh, E. S.; Hamilton, K.; Buser, C. A.; Mao, X.; Abrams, M. T.; Beck, S. C.; Tao, W.; Lobell, R; Sepp-Lorenzino, L.; Zugay-Murphy, J.; Sardana, V.; Munshi, S. K.; Jezequel-Sur, S. M.; Zuck, P. D.; Hartman, G D. Development of thioquinazolinones, allosteric Chk1 kinase inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 1240-1244.
32. Ma, C. X.; Janetka, J. W.; Piwnica-Worms, H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends. Mol. Med. 2011, 17, 88-96.
33. Matthews, T. P.; Klair, S.; Burns, S.; Boxall, K.; Cherry, M.; Fisher, M.; Westwood, I. M.; Walton, M. I.; McHardy, T.; Cheung, K.M. J.; Van Montfort, R; Williams, D.; Aherne, G W.; Garrett, M. D.; Reader, J.; Collins, I. Identification of inhibitors of checkpoint kinase 1 through template screening. J. Med. Chem. 2009, 52, 4810-4819.
34. Matthews, T. P.; McHardy, T.; Klair, S.; Boxall, K.; Fisher, M.; Cherry, M.; Allen, C. E.; Addison, G J.; Ellard, J.; Aherne, G W.; Westwood, I. M.; Montfort, R v.; Garrett, M. D.; Reader, J. C.; Collins, I. Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases. Bioorg. Med. Chem. Lett. 2010, 20, 4045-4049.
35. Antoni, L.; Sodha, N.; Collins, I.; Garrett, M. D. CHK2 kinase: cancer susceptibility and cancer therapy-two sides of the same coin? Nat. Rev. Cancer 2007, 7, 925-936.
36. Guzi, T. J.; Paruch, K.; Dwyer, M. P.; Labroli, M.; Shanahan, F.; Davis, N.; Taricani, L.; Wiswell, D.; Seghezzi, W.; Penaflor, E.; Bhagwat, B.; Wang, W.; Gu, D.; Hsieh, Y.; Lee, S.; Liu, M.; Parry, D. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol. Cancer Ther. 2011, 10, 591-602.
37. Hopkins, A. L.; Groom, C. R; Aex, A Ligand efficency: A useful tool for metric lead selection. Drug Discovery Today 2004, 9, 430-431.
38. Collins, I.; Reader, J. C.; Cheung, K. M.; Matthews, T. P.; Proisy, N.; Klair, S. S. Morpholino-bicyclo-heteroaryl compounds as CHK1 kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. Patent Appl. WO2008075007, 2008; Chem Abstr. 2008, 149, 104737
39. Cherry, M.; Williams, D. H. Recent kinase and kinase inhibitor X-ray structures: Mechanisms of inhibition and selectivity insights. Curr. Med. Chem. 2004, 11, 663-673.
40. Anand, N. K.; Blazey, C. M.; Bowles, O. J.; Bussenius, J.; Canne Bannen, L.; Chan, D. S.-M.; Chen, B.; Co, E. W.; Costanzo, S.; Defina, S. C.; Dubenko, L.; Franzini, M.; Huang, P.; Jammalamadaka, V.; Khoury, R. G.; Kim, M. H.; Klein, R. R.; Le, D. T.; Mac, M. B.; Nuss, J. M.; Parks, J. J.; Rice, K. D.; Tsang, T. H.; Tsuhako, A. L.; Wang, Y.; Xu, W. Preparation and structure activity of pyrazolo-pyrimidine derivatives as antitumor agents and kinase modulators. Patent WO 2005117909, 2005; Chem Abstr. 2006, 144, 104737
41. Bold, G.; Frei, J.; Lang, M.; Traxler, P.; Furet, P. Preparation of pyrazolo[3,4-d]pyrimidines as antitumor agents. Patent WO 9814449, 1998; Chem Abstr. 1998, 128, 282843.
42. Caldwell, J. J.; Davies, T. G.; Donald, A.; McHardy, T.; Rowlands, M. G.; Aherne, G. W.; Hunter, L. K.; Taylor, K.; Ruddle, R.; Raynaud, F. I.; Verdonk, M.; Workman, P.; Garrett, M. D.; Collins, I. Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J. Med. Chem. 2008, 51, 2147-2157.
43. Hoehn, H.; Denzel, T. 1H-Pyrazolo[3,4-b]pyridines. Patent DE 2301268, 1973; Chem Abstr. 1973, 79, 115578.
44. McHardy, T.; Caldwell, J. J.; Cheung, K. M.; Hunter, L. J.; Taylor, K.; Rowlands, M.; Ruddle, R.; Henley, A.; de Haven Brandon, A.; Valenti, M.; Davies, T. G.; Fazal, L.; Seavers, L.; Raynaud, F. I.; Eccles, S. A.; Aherne, G. W.; Garrett, M. D.; Collins, I. Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J. Med. Chem. 2010, 53, 2239-2249.
45. Traxler, P.; Bold, G.; Frei, J.; Lang, M.; Lydon, N.; Mett, H.; Buchdunger, E.; Meyer, T.; Mueller, M.; Furet, P. Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(Phenylamino)pyrazolo[3,4- d]pyrimidines. J. Med. Chem. 1997, 40, 3601-3616.
46. Traxler, P.; Furet, P.; Bold, G.; Frei, J.; Lang, M. Preparation of 4-amino-1H-pyrazolo[3,4-d]pyrimidines as EGF-receptor-specific protein tyrosine kinase inhibitors. Patent WO 9631510, 1996; Chem Abstr. 1997, 126, 8129.
47. Collins, I.; Reader, J. C.; Klair, S.; Scanlon, J.; Addison, G.; Cherry, M. Preparation of 9H-pyrimido[4,5-b]indole, 9H-pyrido-[4′,3′:4,5] pyrrolo[2,3-d]pyridine and 9H-1,3,6,9-tetraazafluorene derivatives as CHK1 kinase inhibitors. Patent WO 2009004329, 2009; Chem Abstr. 2009, 150, 98355.
48. Wang, G. T.; Li, G.; Mantei, R. A.; Chen, Z.; Kovar, P.; Gu, W.; Xiao, Z.; Zhang, H.; Sham, H. L.; Sowin, T.; Rosenberg, S. H.; Lin, N.H. 1-(5-Chloro-2-alkoxyphenyl)-3-(5-cyano-pyrazin-2-yl)ureas as potent and selective inhibitors of Chk1 kinase: Synthesis, preliminary SAR, and biological activities. J. Med. Chem. 2005, 48, 3118-3121.
49. Li, G.; Hasvold, L. A.; Tao, Z.-F.; Wang, G. T.; Gwaltney, S. L. II; Patel, J.; Kovar, P.; Credo, R. B.; Chen, Z.; Zhang, H.; Park, C.; Sham, H. L.; Sowin, T.; Rosenberg, S. H.; Lin, N.-H. Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 2293-2298.
50. Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Halogen bonds in biological molecules. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 16789-16794.
51. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 1990, 82, 1107-1112.
52. Kunimoto, T.; Nitta, K.; Tanaka, T.; Uehara, N.; Baba, H.; Takeuchi, M.; Yokokura, T.; Sawada, S.; Miyasaka, T.; Mutai, M. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res. 1987, 47, 5944-5947.
53. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP methods. J. Phys. Chem. A 1998, 102, 3762-3772.
54. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 2000, 43, 3714-3717.
55. PipelinePilot, version 7.0; Accelrys: San Diego, CA, USA, http://accelrys.com.
56. The National Centre for Protein Kinase Profiling, MRC Protein Phosphorylation Unit, University of Dundee, U.K. (http://www.kinase-screen.mrc. ac.uk)
57. Matthews, D. J.; Yakes, F. M.; Chen, J.; Tadano, M.; Bornheim, L.; Clary, D. O.; Tai, A.; Wagner, J. M.; Miller, N.; Kim, Y. D.; Robertson, S.; Murray, L.; Karnitz, L. M. Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 2007, 6, 104-110.
58. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science 2002, 298, 1912-1934.
59. see: Workman, P.; Aboagye, E. O.; Balkwill, F.; Balmain, A.; Bruder, G.; Chaplin, D. J.; Double, J. A.; Everitt, J.; Farningham, D. A.; Glennie, M. J.; Kelland, L. R.; Robinson, V.; Stratford, I. J.; Tozer, G. M.; Watson, S.; Wedge, S. R.; Eccles, S. A. Committee of the National Cancer Research Institute. Guidelines for the welfare and use of animals in cancer research. Br. J. Cancer 2010, 102, 1555-1577.
60. Collins, I.; Reader, J. C.; Williams, D. H.; Klair, S. S.; Scanlon, J. E.; Piton, N.; Cherry, M. Bicyclylaryl-aryl-amine compounds, their preparation, and their use as CHK1 kinase inhibitors for treating proliferative diseases. Patent WO 2009103966, 2009; Chem Abstr. 2009, 151, 289187.
61. Ventura, B.; Barigelletti, F.; Durola, F.; Flamigni, L.; Sauvage, J.-P.; Wenger, O. S. Fe(II), Ru(II) and Re(I) complexes of endotopic, sterically non-hindering, U-shaped 8,8′-disubstituted-3,3′-biisoquinoline ligands: syntheses and spectroscopic properties. Dalton Trans. 2008, 491-498.