Development and binding mode assessment of N-[4-[2-Propyn-1-yl[(6 S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl] amino]benzoyl]-L-γ-glutamyl-D-glutamic acid (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells

Journal of Medicinal Chemistry

Volumn 56, Issue 13, 2013, Pages 5446-5455

  Tochowicz, Anna ^a   Dalziel, Sean ^b   Eidam, Oliv ^a   O'Connell III, Joseph D ^a   Griner, Sarah ^a,c   Finer Moore, Janet S ^a   Stroud, Robert M ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b ONYX PHARMACEUTICALS   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

10 PROPARGYL 5,8 DIDEAZAFOLIC ACID; ANTINEOPLASTIC AGENT; BGC 45; CELL SURFACE RECEPTOR; DEOXYURIDINE PHOSPHATE; FOLATE RECEPTOR; GLYCOPROTEIN; MAGNESIUM; N [4 [2 PROPYN 1 YL (4,6,7,8 TETRAHYDRO 2 (HYDROXYMETHYL) 4 OXO 3H CYCLOPENTA[ G ]QUINAZOLIN 6 YL]AMINO]BENZOYL] GLUTAMYL DEXTRO GLUTAMIC ACID; ONX 0801; PEMETREXED; PLEVITREXED; RALTITREXED; THYMIDYLATE SYNTHASE; THYMIDYLATE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CRYSTAL STRUCTURE; DRUG BINDING; DRUG EFFICACY; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; ESCHERICHIA COLI; HUMAN; LUNG CANCER; NONHUMAN; OVARY TUMOR; PROTEIN EXPRESSION; TUMOR CELL;

CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; ESCHERICHIA COLI; ESCHERICHIA COLI PROTEINS; FOLIC ACID ANTAGONISTS; HUMANS; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEOPLASMS; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; QUINAZOLINES; THYMIDYLATE SYNTHASE;

EID: 84880154531     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400490e     Document Type: Article

References (52)

1. Heidelberger, C.; Danenberg, P. V.; Moran, R. G. Fluorinated pyrimidines and their nucleosides Adv. Enzymol. Relat. Areas Mol. Biol. 1983, 54, 58-119
2. Santi, D. V.; Danenberg, P. V. Folates in Pyrimidine Nucleotide Biosynthesis. In Folates and Pterins; Blakley, R. L.; Benkovik, S. J., Eds.; John Wiley and Sons: New York, 1984; Vol. 1, pp 345-398.
3. Jackman, A. L.; Newell, D. R.; Gibson, W.; Jodrell, D. I.; Taylor, G. A.; Bishop, J. A.; Hughes, L. R.; Calvert, A. H. The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8- dideazafolic acid (ICI 198583) Biochem. Pharmacol. 1991, 42, 1885-1895
4. Stout, T. J.; Stroud, R. M. The complex of the anti-cancer therapeutic, BW1843U89, with thymidylate synthase at 2.0 A resolution: implications for a new mode of inhibition Structure 1996, 4, 67-77
5. Stout, T. J.; Tondi, D.; Rinaldi, M.; Barlocco, D.; Pecorari, P.; Santi, D. V.; Kuntz, I. D.; Stroud, R. M.; Shoichet, B. K.; Costi, M. P. Structure-based design of inhibitors specific for bacterial thymidylate synthase Biochemistry 1999, 38, 1607-1617
6. Almog, R.; Waddling, C. A.; Maley, F.; Maley, G. F.; Van Roey, P. Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP Protein Sci. 2001, 10, 988-996
7. Sayre, P. H.; Finer-Moore, J. S.; Fritz, T. A.; Biermann, D.; Gates, S. B.; MacKellar, W. C.; Patel, V. F.; Stroud, R. M. Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases J. Mol. Biol. 2001, 313, 813-829
8. Montfort, W. R.; Perry, K. M.; Fauman, E. B.; Finer-Moore, J. S.; Maley, G. F.; Hardy, L.; Maley, F.; Stroud, R. M. Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folate Biochemistry 1990, 29, 6964-6977
9. Matthews, D. A.; Appelt, K.; Oatley, S. J.; Xuong, N. H. Crystal structure of Escherichia coli thymidylate synthase containing bound 5-fluoro-2′-deoxyuridylate and 10-propargyl-5,8-dideazafolate J. Mol. Biol. 1990, 214, 923-936
10. Jackman, A. L.; Taylor, G. A.; Gibson, W.; Kimbell, R.; Brown, M.; Calvert, A. H.; Judson, I. R.; Hughes, L. R. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: A new agent for clinical study Cancer Res. 1991, 51, 5579-5586
11. Farrugia, D. C.; Ford, H. E.; Cunningham, D.; Danenberg, K. D.; Danenberg, P. V.; Brabender, J.; McVicar, A. D.; Aherne, G. W.; Hardcastle, A.; McCarthy, K.; Jackman, A. L. Thymidylate synthase expression in advanced colorectal cancer predicts for response to raltitrexed Clin. Cancer Res. 2003, 9, 792-801
12. Jarmula, A. Antifolate inhibitors of thymidylate synthase as anticancer drugs Mini Rev. Med. Chem. 2010, 10, 1211-1222
13. Jackman, A. L.; Forster, M.; Ng, M. Targeting thymidylate synthase by antifolate drugs for the treatment of cancer. In Cancer Drug Design and Discovery; Neidle, S., Ed.; Elsevier: New York, 2007; pp 198-226.
14. Jones, T. R.; Calvert, A. H.; Jackman, A. L.; Brown, S. J.; Jones, M.; Harrap, K. R. A potent antitumour quinazoline inhibitor of thymidylate synthetase: synthesis, biological properties and therapeutic results in mice Eur. J. Cancer 1981, 17, 11-19
15. Clarke, S. J.; Jackman, A. L.; Judson, I. R. The history of the development and clinical use of CB 3717 and ICI D1694 Adv. Exp. Med. Biol. 1993, 339, 277-287
16. Discussion. 289-290.
17. Wilson, K. S.; Fitzgerald, C. A.; Barnett, J. B.; Gill, S.; Khoo, K. E. Adjuvant therapy with raltitrexed in patients with colorectal cancer intolerant of 5-fluorouracil: British Columbia Cancer Agency experience Cancer Invest. 2007, 25, 711-714
18. Wilson, K. S.; Malfair Taylor, S. C. Raltitrexed: optimism and reality Expert Opin. Drug Metab. Toxicol. 2009, 5, 1447-1454
19. Walling, J. From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates Invest. New Drugs 2006, 24, 37-77
20. Goldman, I. D.; Zhao, R. Molecular, biochemical, and cellular pharmacology of pemetrexed Semin. Oncol. 2002, 29, 3-17
21. Adjei, A. A. Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent Clin. Cancer Res. 2004, 10, 4276s-4280s
22. Adjei, A. A. Clinical studies of pemetrexed and gemcitabine combinations Ann. Oncol. 2006, 17 (Suppl 5) v29-32
23. Tomao, F.; Panici, P. B.; Frati, L.; Tomao, S. Emerging role of pemetrexed in ovarian cancer Expert Rev. Anticancer Ther. 2009, 9, 1727-1735
24. Scagliotti, G. V.; Shin, D. M.; Kindler, H. L.; Vasconcelles, M. J.; Keppler, U.; Manegold, C.; Burris, H.; Gatzemeier, U.; Blatter, J.; Symanowski, J. T.; Rusthoven, J. J. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma J. Clin. Oncol. 2003, 21, 1556-1561
25. Vogelzang, N. J.; Rusthoven, J. J.; Symanowski, J.; Denham, C.; Kaukel, E.; Ruffie, P.; Gatzemeier, U.; Boyer, M.; Emri, S.; Manegold, C.; Niyikiza, C.; Paoletti, P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma J. Clin. Oncol. 2003, 21, 2636-2644
26. Chattopadhyay, S.; Moran, R. G.; Goldman, I. D. Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications Mol. Cancer Ther. 2007, 6, 404-417
27. Theti, D. S.; Jackman, A. L. The role of alpha-folate receptor-mediated transport in the antitumor activity of antifolate drugs Clin. Cancer Res. 2004, 10, 1080-1089
28. Gibbs, D. D.; Theti, D. S.; Wood, N.; Green, M.; Raynaud, F.; Valenti, M.; Forster, M. D.; Mitchell, F.; Bavetsias, V.; Henderson, E.; Jackman, A. L. BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors Cancer Res. 2005, 65, 11721-11728
29. Jackman, A. L.; Theti, D. S.; Gibbs, D. D. Antifolates targeted specifically to the folate receptor Adv Drug Delivery Rev. 2004, 56, 1111-1125
30. Elnakat, H.; Ratnam, M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy Adv. Drug Delivery Rev. 2004, 56, 1067-1084
31. Pillai, R. G.; Forster, M.; Perumal, M.; Mitchell, F.; Leyton, J.; Aibgirhio, F. I.; Golovko, O.; Jackman, A. L.; Aboagye, E. O. Imaging pharmacodynamics of the alpha-folate receptor-targeted thymidylate synthase inhibitor BGC 945 Cancer Res. 2008, 68, 3827-3834
32. Henderson, E. A.; Bavetsias, V.; Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A. L. Targeting the alpha-folate receptor with cyclopenta[g] quinazoline-based inhibitors of thymidylate synthase Bioorg. Med. Chem. 2006, 14, 5020-5042
33. Bavetsias, V.; Marriott, J. H.; Melin, C.; Kimbell, R.; Matusiak, Z. S.; Boyle, F. T.; Jackman, A. L. Design and synthesis of cyclopenta[ g ]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents J. Med. Chem. 2000, 43, 1910-1926
34. Bavetsias, V.; Jackman, A. L.; Kimbell, R.; Gibson, W.; Boyle, F. T.; Bisset, G. M. Quinazoline antifolate thymidylate synthase inhibitors: gamma-linked l-d, d-d, and d-l dipeptide analogues of 2-desamino-2-methyl-N10- propargyl-5,8-dideazafolic acid (ICI 198583) J. Med. Chem. 1996, 39, 73-85
35. Jodrell, D. I.; Gibson, W.; Bisset, G. M.; Boyle, F. T.; Judson, I. R.; Jackman, A. L. The in vivo metabolic stability of dipeptide analogues of the quinazoline antifolate, ICI 198583, in mice Biochem. Pharmacol. 1993, 46, 2229-2234
36. Onyx Pharmaceuticals. Efficient peptide couplings and their use in the synthesis and isolation of a cyclopenta[g]quinazoline trisodium salt. Application No. PCT/US2011/065752, Publication No. WO 2012/087888 A2, January 28, 2012.
37. Onyx Pharmaceuticals. Synthesis of cyclopentaquinazolines. Application No. PCT/US2011/001235, Publication No. WO 2012/011939 A2, January 26, 2012.
38. Reich, S. H.; Fuhry, M. A.; Nguyen, D.; Pino, M. J.; Welsh, K. M.; Webber, S.; Janson, C. A.; Jordan, S. R.; Matthews, D. A.; Smith, W. W. Design and synthesis of novel 6,7-imidazotetrahydroquinoline inhibitors of thymidylate synthase using iterative protein crystal structure analysis J. Med. Chem. 1992, 35, 847-858
39. Phan, J.; Koli, S.; Minor, W.; Dunlap, R. B.; Berger, S. H.; Lebioda, L. Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug Biochemistry 2001, 40, 1897-1902
40. Spencer, H. T.; Villafranca, J. E.; Appleman, J. R. Kinetic scheme for thymidylate synthase from Escherichia coli: determination from measurements of ligand binding, primary and secondary isotope effects, and pre-steady-state catalysis Biochemistry 1997, 36, 4212-4222
41. Kamb, A.; Finer-Moore, J.; Calvert, A. H.; Stroud, R. M. Structural basis for recognition of polyglutamyl folates by thymidylate synthase Biochemistry 1992, 31, 9883-9890
42. Laskowski, R. A.; Swindells, M. B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery J Chem. Inf. Model. 2011, 51, 2778-2786
43. Maley, G. F.; Maley, F.; Baugh, C. M. Differential inhibition of host and viral thymidylate synthetases by folylpolyglutamates J. Biol. Chem. 1979, 254, 7485-7487
44. 2+ binds to the surface of thymidylate synthase and affects hydride transfer at the interior active site J. Am. Chem. Soc. 2013, 135, 7583-7592
45. Boles, J. O.; Cisneros, R. J.; Weir, M. S.; Odom, J. D.; Villafranca, J. E.; Dunlap, R. B. Purification and characterization of selenomethionyl thymidylate synthase from Escherichia coli: Comparison with the wild-type enzyme Biochemistry 1991, 30, 11073-11080
46. Carosati, E.; Tochowicz, A.; Marverti, G.; Guaitoli, G.; Benedetti, P.; Ferrari, S.; Stroud, R. M.; Finer-Moore, J.; Luciani, R.; Farina, D.; Cruciani, G.; Costi, M. P. Inhibitor of ovarian cancer cells growth by virtual screening: A new thiazole derivative targeting human thymidylate synthase J. Med. Chem. 2012, 55, 10272-10276
47. Kabsch, W. Integration, scaling, space-group assignment and post-refinement Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 133-144
48. Storoni, L. C.; McCoy, A. J.; Read, R. J. Likelihood-enhanced fast rotation functions Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 432-438
49. Adams, P. D.; Grosse-Kunstleve, R. W.; Hung, L. W.; Ioerger, T. R.; McCoy, A. J.; Moriarty, N. W.; Read, R. J.; Sacchettini, J. C.; Sauter, N. K.; Terwilliger, T. C. PHENIX: building new software for automated crystallographic structure determination Acta Crystallogr., Sect. D: Biol. Crystallogr. 2002, 58, 1948-1954
50. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2126-2132
51. Kalyanaraman, C.; Bernacki, K.; Jacobson, M. P. Virtual screening against highly charged active sites: identifying substrates of alpha-beta barrel enzymes Biochemistry 2005, 44, 2059-2071
52. Sherman, W.; Day, T.; Jacobson, M. P.; Friesner, R. A.; Farid, R. Novel procedure for modeling ligand/receptor induced fit effects J. Med. Chem. 2006, 49, 534-553