Combining hit identification strategies: Fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone

Journal of Medicinal Chemistry

Volumn 52, Issue 15, 2009, Pages 4794-4809

  Brough, Paul A ^a   Barril, Xavier ^a   Borgognoni, Jenifer ^a   Chene, Patrick ^c   Davies, Nicholas G M ^a   Davis, Ben ^a   Drysdale, Martin J ^a   Dymock, Brian ^a   Eccles, Suzanne A ^b   Garcia Echeverria, Carlos ^c   Fromont, Christophe ^a   Hayes, Angela ^b   Hubbard, Roderick E ^a   Jordan, Allan M ^a   Jensen, Michael Rugaard ^c   Massey, Andrew ^a   Merrett, Angela ^a   Padfield, Antony ^a   Parsons, Rachel ^a   Radimerski, Thomas ^c   Raynaud, Florence I ^b   Robertson, Alan ^a   Roughley, Stephen D ^a   Schoepfer, Joseph ^c   Simmonite, Heather ^a   Sharp, Swee Y ^b   Surgenor, Allan ^a   Valenti, Melanie ^b   Walls, Steven ^a   Webb, Paul ^a   Wood, Mike ^a   Workman, Paul ^b   Wright, Lisa ^a   more..

^a Vernalis PLC   (United Kingdom)

^b IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

^c NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 4 [2,4 DICHLORO 5 (1 ETHYLPYRROLIDIN 3 YLOXY)PHENYL]THIENO[2,3 D]PYRIMIDINE 6 CARBOXYLIC ACID ETHYLAMIDE; 2 AMINO 4 [2,4 DICHLORO 5 (2 DIETHYLAMINOETHOXY)PHENYL]THIENO[2,3 D]PYRIMIDINE 6 CARBOXYLIC ACID ETHYLAMIDE; 2 AMINO 4 [2,4 DICHLORO 5 (2 PYRROLIDIN 1 YLETHOXY)PHENYL]THIENO[2,3 D]PYRIMIDINE 6 CARBOXYLIC ACID ETHYLAMIDE; HEAT SHOCK PROTEIN 72; HEAT SHOCK PROTEIN 90; THIENO[2,3 D]PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER CELL CULTURE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG SYNTHESIS; DRUG TOLERABILITY; FLUORESCENCE POLARIZATION; HUMAN; HUMAN CELL; MALE; MOUSE; NONHUMAN; TUMOR REGRESSION; TUMOR XENOGRAFT; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; ANTINEOPLASTIC AGENTS; BINDING, COMPETITIVE; CRYSTALLOGRAPHY, X-RAY; FEMALE; FLUORESCENCE POLARIZATION; HSP90 HEAT-SHOCK PROTEINS; HUMANS; MALE; MICE; MICE, INBRED BALB C; PYRIMIDINES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 68549115383     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900357y     Document Type: Article

References (84)

1. Mosser, D. D.; Morimoto, R. I. Molecular chaperones and the stress of oncogenesis. Oncogene 2004, 23, 2907-2918.
2. Pearl, L. H.; Prodromou, C. Structure and mechanism of the hsp90 molecular chaperone machinery. Annu. Rev. Biochem. 2006, 75, 271-294.
3. Obermann, W. M.; Sondermann, H.; Russo, A. A.; Pavletich, N. P.; Hartl, F. U. In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J. Cell Biol. 1998, 143, 901-910.
4. Panaretou, B.; Prodromou, C.; Roe, S. M.; O'Brien, R.; Ladbury, J. E.; Piper, P. W.; Pearl, L. H. ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J. 1998, 17, 4829-4836.
5. Pearl, L. H.; Prodromou, C.; Workman, P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem. J. 2008, 410, 439-453.
6. For a list, see the web page maintained by D. Picard: http://www. picard.ch/downloads/Hsp90interactors.pdf. Accessed on July 13, 2009
7. Whitesell, L.; Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761-772.
8. Maloney, A.; Workman, P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin.Biol. Ther. 2002, 2, 3-24.
9. Kamal, A.; Boehm, M. F.; Burrows, F. J. Therapeutic and diagnostic implications of Hsp90 activation. Trends Mol. Med. 2004, 10, 283-290.
10. Chiosis, G.; Vilenchik, M.; Kim, J.; Solit, D. Hsp90: the vulnerable chaperone. Drug Discovery Today 2004, 9, 881-888.
11. Hanahan, D.; Weinberg, R. A. The hallmarks of cancer. Cell 2000, 100, 57-70.
12. Workman, P. Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett. 2004, 206, 149-157.
13. DeBoer, C.; Meulman, P. A.; Wnuk, R. J.; Peterson, D. H. Geldanamycin, a new antibiotic. J. Antibiot. (Tokyo) 1970, 23, 442-447.
14. Supko, J. G.; Hickman, R. L.; Grever, M. R.; Malspeis, L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol. 1995, 36, 305-315.
15. Neckers, L.; Schulte, T. W.; Mimnaugh, E. Geldanamycin as a potential anticancer agent: its molecular target and biochemical activity. Invest. New Drugs 1999, 17, 361-373.
16. Delmotte, P.; Delmotte-Plaque, J. A new antifungal substance of fungal origin. Nature 1953, 171, 344.
17. Soga, S.; Shiotsu, Y.; Akinaga, S.; Sharma, S. V. Development of radicicol analogues. Curr. Cancer Drug Targets 2003, 3, 359-369.
18. Roe, S. M.; Prodromou, C.; O'Brien, R.; Ladbury, J. E.; Piper, P. W.; Pearl, L. H. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. 1999, 42, 260-266.
19. Hostein, I.; Robertson, D.; DiStefano, F.; Workman, P.; Clarke, P. A. Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17- demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res. 2001, 61, 4003-4009.
20. Schulte, T. W.; Neckers, L. M. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother. Pharmacol. 1998, 42, 273-279.
21. Banerji, U.; O'Donnell, A.; Scurr, M.; Pacey, S.; Stapleton, S.; Asad, Y.; Simmons, L.; Maloney, A.; Raynaud, F.; Campbell, M.; Walton, M.; Lakhani, S.; Kaye, S.; Workman, P.; Judson, I. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J. Clin. Oncol. 2005, 23, 4152-4161.
22. Goetz, M. P.; Toft, D.; Reid, J.; Ames, M.; Stensgard, B.; Safgren, S.; Adjei, A. A.; Sloan, J.; Atherton, P.; Vasile, V.; Salazaar, S.; Adjei, A.; Croghan, G.; Erlichman, C. Phase I trial of 17-allylamino-17- demethoxygeldanamycin in patients with advanced cancer. J. Clin. Oncol. 2005, 23, 1078-1087.
23. Weigel, B. J.; Blaney, S. M.; Reid, J. M.; Safgren, S. L.; Bagatell, R.; Kersey, J.; Neglia, J. P.; Ivy, S. P.; Ingle, A. M.; Whitesell, L.; Gilbertson, R. J.; Krailo, M.; Ames, M.; Adamson, P. C. APhase I Study of 17-Allylaminogeldanamycin in Relapsed/Refractory Pediatric Patients with Solid Tumors: A Children's Oncology Group Study. Clin. Cancer Res. 2007, 13, 1789-1793.
24. Solit, D. B.; Osman, I.; Polsky, D.; Panageas, K. S.; Daud, A.; Goydos, J. S.; Teitcher, J.; Wolchok, J. D.; Germino, F. J.; Krown, S. E.; Coit, D.; Rosen, N.; Chapman, P. B. Phase II Trial of 17-Allylamino-17- Demethoxygeldanamycin in Patients with Metastatic Melanoma. Clin. Cancer Res. 2008, 14, 8302-8307.
25. Kamal, A.; Thao, L.; Sensintaffar, J.; Zhang, L.; Boehm, M. F.; Fritz, L. C.; Burrows, F. J. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003, 425, 407-410.
26. da Rocha, D. S.; Friedlos, F.; Light, Y.; Springer, C.; Workman, P.; Marais, R. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 2005, 65, 10686-10691.
27. Workman, P.; Burrows, F.; Neckers, L. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann. N.Y. Acad. Sci. 2007, 1113, 202-216.
28. Egorin, M. J.; Rosen, D. M.; Wolff, J. H.; Callery, P. S.; Musser, S. M.; Eiseman, J. L. Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res. 1998, 58, 2385-2396.
29. Kelland, L. R.; Sharp, S. Y.; Rogers, P. M.; Myers, T. G.; Workman, P. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J. Natl. Cancer Inst. 1999, 91, 1940-1949.
30. Meli, M.; Pennati, M.; Curto, M.; Daidone, M. G.; Plescia, J.; Toba, S.; Altieri, D. C.; Zaffaroni, N.; Colombo, G. Small-Molecule Targeting of Heat Shock Protein 90 Chaperone Function: Rational Identification of a New Anticancer Lead. J. Med. Chem. 2006, 49, 7721-7730.
31. Gaspar, N.; Sharp, S. Y.; Pacey, S.; Jones, D.; Walton, M.; Vassal, G.; Eccles, S.; Pearson, A.; Workman, P. Acquired Resistance to 17-Allylamino-17- Demethoxygeldanamycin (Tanespimycin) in Glioblastoma Cells. Cancer Res. 2009, 69, 1966-1975.
32. Kaur, G.; Belotti, D.; Burger, A. M.; Fisher-Nielson, K.; Borsotti, P.; Riccardi, E.; Thillainathan, J.; Hollingshead, M.; Sausville, E. A.; Giavazzi, R. Antiangiogenic properties of 17-(dimethylaminoethylamino)-17- demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator. Clin. Cancer Res. 2004, 10, 4813-4821.
33. Ge, J.; Normant, E.; Porter, J. R.; Ali, J. A.; Dembski, M. S.; Gao, Y.; Georges, A. T.; Grenier, L.; Pak, R. H.; Patterson, J.; Sydor, J. R.; Tibbitts, T. T.; Tong, J. K.; Adams, J.; Palombella,V. J. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17- demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J. Med. Chem. 2006, 49, 4606-4615.
34. Sydor, J. R.; Normant, E.; Pien, C. S.; Porter, J. R.; Ge, J.; Grenier, L.; Pak, R. H.; Ali, J. A.; Dembski, M. S.; Hudak, J.; Patterson, J.; Penders, C.; Pink, M.; Read, M. A.; Sang, J.; Woodward, C.; Zhang, Y.; Grayzel, D. S.; Wright, J.; Barrett, J. A.; Palombella, V. J.; Adams, J.; Tong, J. K. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anticancer agent directed against Hsp90. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 17408-17413.
35. Modi, S.; Stopeck, A. T.; Gordon, M. S.; Mendelson, D.; Solit, D. B.; Bagatell, R.; Ma, W.; Wheler, J.; Rosen, N.; Norton, L.; Cropp, G. F.; Johnson, R. G.; Hannah, A. L.; Hudis, C. A. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2-overexpressing breast cancer: a phase I dose-escalation study. J. Clin. Oncol. 2007, 25, 5410-5417.
36. Drysdale, M. J.; Brough, P. A. Medicinal chemistry of Hsp90 inhibitors. Curr. Top. Med. Chem. 2008, 8, 859-868.
37. Chiosis, G. Discovery and development of purine-scaffold Hsp90 inhibitors. Curr. Top. Med. Chem. 2006, 6, 1183-1191.
38. Chiosis, G.; Rodina, A.; Moulick, K. Emerging Hsp90 inhibitors: from discovery to clinic. Anticancer Agents Med. Chem. 2006, 6, 1-8.
39. Chiosis, G.; Lopes, E. C.; Solit, D. Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents. Curr. Opin. Invest. Drugs (Thomson Scientific) 2006, 7, 534-541.
40. Dymock, B. W.; Drysdale, M. J.; McDonald, E.; Workman, P. Inhibitors of HSP90 and other chaperones for the treatment of cancer. Expert Opin. Ther. Pat. 2004, 14, 837-847.
41. Neckers, L.; Neckers, K. Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics;an update. Expert Opin. Emerging Drugs 2005, 10, 137-149.
42. Janin, Y. L. Heat shock protein 90 inhibitors.A text book example of medicinal chemistry?. J. Med. Chem. 2005, 48, 7503-7512.
43. Drysdale, M. J.; Brough, P. A.; Massey, A.; Jensen, M. R.; Schoepfer, J. Targeting Hsp90 for the treatment of cancer. Curr. Opin. Drug Discovery Dev. 2006, 9, 483-495.
44. McDonald, E.; Workman, P.; Jones, K. Inhibitors of the HSP90 molecular chaperone: attacking the master regulator in cancer. Curr. Top. Med. Chem. 2006, 6, 1091-1107.
45. Messaoudi, S.; Peyrat, J. F.; Brion, J. D.; Alami, M. Recent advances in Hsp90 inhibitors as antitumor agents. Anti-Cancer Agents Med. Chem. 2008, 8, 761-782.
46. Taldone, T.; Gozman, A.; Maharaj, R.; Chiosis, G. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr. Opin. Pharmacol. 2008, 8, 370-374.
47. Taldone, T.; Sun, W.; Chiosis, G. Discovery and development of heat shock protein 90 inhibitors. Bioorg. Med. Chem. 2009, 17, 2225-2235.
48. Kasibhatla, S. R.; Hong, K.; Biamonte, M. A.; Busch, D. J.; Karjian, P. L.; Sensintaffar, J. L.; Kamal, A.; Lough, R. E.; Brekken, J.; Lundgren, K.; Grecko, R.; Timony, G. A.; Ran, Y.; Mansfield, R.; Fritz, L. C.; Ulm, E.; Burrows, F. J.; Boehm, M. F. Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J. Med. Chem. 2007, 50, 2767-2778.
49. Lundgren, K.; Zhang, H.; Brekken, J.; Huser, N.; Powell, R. E.; Timple, N.; Busch, D. J.; Neely, L.; Sensintaffar, J. L.; Yang, Y. C.; McKenzie, A.; Friedman, J.; Scannevin, R.; Kamal, A.; Hong, K.; Kasibhatla, S. R.; Boehm, M. F.; Burrows, F. J. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol. Cancer Ther. 2009, 8, 921-929.
50. (a) Chandarlapaty, S.; Sawai, A.; Ye, Q.; Scott, A.; Silinski, M.; Huang, K.; Fadden, P.; Partdrige, J.; Hall, S.; Steed, P.; Norton, L.; Rosen, N.; Solit, D. B. SNX2112, a Synthetic Heat Shock Protein 90 Inhibitor, Has Potent Antitumor Activity against HER Kinase-Dependent Cancers. Clin. Cancer Res. 2008, 14, 240-248.
51. (b) Huang, K. H.;Veal, J. M.; Fadden, R. P.; Rice, J.W.; Eaves, J.; Strachan, J. P.; Barabasz, A. F.; Foley, B. E.; Barta, T. E.; Ma,W.; Silinski, M. A.; Hu, M.; Partridge, J. M.; Scott, A.; Dubois, L. G.; Freed, T.; Steed, P. M.; Ommen, A. J.; Smith, E. D.; Hughes, P. F.; Woodward, A. R.; Hanson, G. J.; McCall,W. S.; Markworth, C. J.; Hinkley, L.; Jenks, M.; Geng, L.; Lewis, M.; Otto, J.; Pronk, B.; Verleysen, K.; Hall, S. E. Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents. J. Med. Chem. 2009, 52, 4288-4305.
52. Brough, P. A.; Aherne, W.; Barril, X.; Borgognoni, J.; Boxall, K.; Cansfield, J. E.; Cheung, K. M.; Collins, I.; Davies, N. G.; Drysdale, M. J.; Dymock, B.; Eccles, S. A.; Finch, H.; Fink, A.; Hayes, A.; Howes, R.; Hubbard, R. E.; James, K.; Jordan, A. M.; Lockie, A.; Martins, V.; Massey, A.; Matthews, T. P.; McDonald, E.; Northfield, C. J.; Pearl, L. H.; Prodromou, C.; Ray, S.; Raynaud, F. I.; Roughley, S. D.; Sharp, S. Y.; Surgenor, A.; Walmsley, D. L.; Webb, P.; Wood, M.; Workman, P.; Wright, L. 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J. Med. Chem. 2008, 51, 196-218.
53. Eccles, S. A.; Massey, A.; Raynaud, F. I.; Sharp, S. Y.; Box, G.; Valenti, M.; Patterson, L.; Haven Brandon, A.; Gowan, S.; Boxall, F.; Aherne, W.; Rowlands, M.; Hayes, A.; Martins, V.; Urban, F.; Boxall, K.; Prodromou, C.; Pearl, L.; James, K.; Matthews, T. P.; Cheung, K. M.; Kalusa, A.; Jones, K.; McDonald, E.; Barril, X.; Brough, P. A.; Cansfield, J. E.; Dymock, B.; Drysdale, M. J.; Finch, H.; Howes, R.; Hubbard, R. E.; Surgenor, A.; Webb, P.; Wood, M.; Wright, L.; Workman, P. NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis. Cancer Res. 2008, 68, 2850-2860.
54. See www.clinicaltrials.gov for details of clinical trials relating Hsp90 inhibitors. Accessed on July 13, 2009.
55. Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent developments in fragment-based drug discovery. J. Med. Chem. 2008, 51, 3661-3680.
56. Erlanson, D. A. Fragment-based lead discovery: a chemical update. Curr. Opin. Biotechnol. 2006, 17, 643-652.
57. Hajduk, P. J.; Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discovery 2007, 6, 211-219.
58. Hubbard, R. E. Fragment approaches in structure-based drug discovery. J. Synchrotron Radiat. 2008, 15, 227-230.
59. Jahnke, W. Erlanson, D. A. Fragment-Based Approaches in Drug Discovery; Wiley: Weinheim, Germany, 2007.
60. Jhoti, H. Leach, A. R. Structure-Based Drug Discovery; Springer: Dordrecht, The Netherlands, 2007.
61. Hubbard, R. E.; Davis, B.; Chen, I.; Drysdale, M. J. The SeeDs approach: integrating fragments into drug discovery. Curr. Top. Med. Chem. 2007, 7, 1568-1581.
62. Chiosis, G.; Timaul, M. N.; Lucas, B.; Munster, P. N.; Zheng, F. F.; Sepp-Lorenzino, L.; Rosen, N. A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem. Biol. 2001, 8, 289-299.
63. Lepre, C. A.; Moore, J. M.; Peng, J. W. Theory and applications of NMR-based screening in pharmaceutical research. Chem. Rev. 2004, 104, 3641-3676.
64. Mayer, M.; Meyer, B. Characterisation of ligand binding by saturation transfer difference NMR spectroscopy. Angew. Chem., Int. Ed. 1999, 38, 1784-1788.
65. Dalvit, C.; Pevarello, P.; Tato, M.; Veronesi, M.; Vulpetti, A.; Sundstrom, M. Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J. Biomol. NMR 2000, 18, 65-68.
66. Hajduk, P. J.; Olejniczak, E. T.; Fesik, S. W. One-Dimensional Relaxation and Diffusion-Edited NMR Methods for Screening Compounds that Bind to Macromolecules. J. Am. Chem. Soc. 1997, 119, 12257-12261.
67. Baurin, N.; Aboul-Ela, F.; Barril, X.; Davis, B.; Drysdale, M.; Dymock, B.; Finch, H.; Fromont, C.; Richardson, C.; Simmonite, H.; Hubbard, R. E. Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets. J. Chem. Inf. Comput. Sci. 2004, 44, 2157-2166.
68. Huth, J. R.; Park, C.; Petros, A. M.; Kunzer, A. R.; Wendt, M. D.; Wang, X.; Lynch, C. L.; Mack, J. C.; Swift, K. M.; Judge, R. A.; Chen, J.; Richardson, P. L.; Jin, S.; Tahir, S. K.; Matayoshi, E. D.; Dorwin, S. A.; Ladror, U. S.; Severin, J. M.; Walter, K. A.; Bartley, D. M.; Fesik, S. W.; Elmore, S. W.; Hajduk, P. J. Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies. Chem. Biol. Drug Des. 2007, 70, 1-12.
69. Barker, J. J.; Barker, O.; Boggio, R.; Chauhan, V.; Cheng, R. K.; Corden, V.; Courtney, S. M.; Edwards, N.; Falke, V. M.; Fusar, F.; Gardiner, M.; Hamelin, E. M.; Hesterkamp, T.; Ichihara, O.; Jones, R. S.; Mather, O.; Mercurio, C.; Minucci, S.; Montalbetti, C. A.; Muller, A.; Patel, D.; Phillips, B. G.; Varessi, M.; Whittaker, M.; Winkler, D.; Yarnold, C. J. Fragment-Based Identification of Hsp90 Inhibitors. ChemMedChem 2009, 4, 963-966.
70. Barril, X.; Brough, P.; Drysdale, M.; Hubbard, R. E.; Massey, A.; Surgenor, A.; Wright, L. Structure-based discovery of a new class of Hsp90 inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 5187-5191.
71. Knox,A. J. S.; Price, T.; Pawlak,M.;Golfis, G.;Flood,C.T.;Fayne, D.; Williams, D. C.; Meegan, M. J.; Lloyd, D. G. Integration of Ligand and Structure-Based Virtual Screening for the Identification of theFirstDualTargetingAgent forHeat Shock Protein 90 (Hsp90) and Tubulin. J. Med. Chem. 2009, 52, 2177-2180.
72. Barril, X.; Hubbard, R. E.; Morley, S. D. Virtual screening in structure-based drug discovery. Mini. Rev. Med. Chem. 2004, 4, 779-791.
73. Wright, L.; Barril, X.; Dymock, B.; Sheridan, L.; Surgenor, A.; Beswick, M.; Drysdale, M.; Collier, A.; Massey, A.; Davies, N.; Fink, A.; Fromont, C.; Aherne, W.; Boxall, K.; Sharp, S.; Workman, P.; Hubbard, R. E. Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms. Chem. Biol. 2004, 11, 775-785.
74. Baurin, N.; Baker, R.; Richardson, C.; Chen, I.; Foloppe, N.; Potter, A.; Jordan, A.; Roughley, S.; Parratt, M.; Greaney, P.; Morley, D.; Hubbard, R. E. Drug-like annotation and duplicate analysis of a 23-supplier chemical database totalling 2.7 million compounds. J. Chem. Inf. Comput. Sci. 2004, 44, 643-651.
75. Howes, R.; Barril, X.; Dymock, B. W.; Grant, K.; Northfield,C. J.; Robertson, A. G.; Surgenor, A.; Wayne, J.; Wright, L.; James, K.; Matthews, T.; Cheung, K. M.; McDonald, E.; Workman, P.; Drysdale, M. J. A fluorescence polarization assay for inhibitors of Hsp90. Anal. Biochem. 2006, 350, 202-213.
76. Wittenbrook, L. S. Chemistry of N-cyanodithioimidocarbonic acid. III. Intermediate in heterocyclic synthesis. J. Heterocycl. Chem. 1975, 12, 37-42.
77. Clark, J.; Shahhet, M. S. Synthesis of thieno[2,3-d]pyrimidines from 4,6-dichloropyrimidine-5-carboxaldehydes. J. Heterocycl. Chem. 1993, 30, 1065-1072.
78. Miyaura, N.; Suzuki, H. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 2005, 95, 2457-2483.
79. Zhu, L.; Duquette, J.; Zhang, M. An Improved Preparation of Arylboronates: Application in One-Pot Suzuki Biaryl Synthesis. J. Org. Chem. 2003, 68, 3729-3732.
80. Hughes, D. L. The Mitsunobu Reaction. Org. React. 1992, 42, 335-656.
81. PDB codes: compound 10 (cocrystal)=2WI2, 10 (soak)=2WI3, 11 =2WI1, 12=2WI4, 13=2WI5, 21e=2WI6, and 34d=2WI7.
82. (a) Dymock, B. W.; Drysdale, M. J.; Fromont, C.; Jordan, A.; Barril-Alonso, X. Preparation of pyrimidothiophenes as HSP90 inhibitors. PCT Int. Appl. WO200500521552, 2005.
83. (b) Brough, P. A.; Barril-Alonso, X.; Drysdale, M. J. Preparation of pyrimidithiophene derivatives for use as HSP90 inhibitors. PCT International Application WO2006090094, 2006.
84. Workman, P.; Twentyman, P.; Balkwill, F.; Balmain, A.; Chaplin, C.; Double, J. United Kingdom Coordinating Committee on Cancer Research guidelines for the welfare of animals in experimental neoplasia, 2nd Ed. Br. J. Cancer 1998, 77, 1-10.