Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases

Journal of Molecular Biology

Volumn 313, Issue 4, 2001, Pages 813-829

  Sayre, Peter H ^a   Finer Moore, Janet S ^a   Fritz, Timothy A ^a   Biermann, Donna ^a   Gates, Susan B ^b   MacKellar, Warren C ^b   Patel, Vinod F ^b   Stroud, Robert M ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

Antifolate; Cancer; Drug resistance; dTMP synthesis; X ray crystal structure

Indexed keywords

10 PROPARGYL 5,8 DIDEAZAFOLIC ACID; FOLIC ACID ANTAGONIST; LY 338529; LY 341770; PEMETREXED; THYMIDYLATE SYNTHASE; THYMIDYLATE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; COMPLEX FORMATION; CONTROLLED STUDY; COVALENT BOND; CRYSTALLIZATION; DRUG DETERMINATION; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME BINDING; ENZYME CONFORMATION; ESCHERICHIA COLI; HUMAN; INHIBITION KINETICS; MOLECULAR INTERACTION; NONHUMAN; PRIORITY JOURNAL; STRUCTURE ANALYSIS; TEMPERATURE DEPENDENCE; X RAY CRYSTALLOGRAPHY;

EID: 0035798375     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1006/jmbi.2001.5074     Document Type: Article

References (53)

1. Fluorinated pyrimidines and their nucleosides
2. Single amino acid substitution defines a naturally occurring genetic variant of human thymidylate synthase
3. Isolation and characterization of Thymitaq (AG337) and 5-fluoro-2-deoxyuridylate-resistant mutants of human thymidylate synthase from ethyl methanesulfonate-exposed human sarcoma HT1080 cells
4. Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism
5. 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
6. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes
7. Biochemical effects of a quinazoline inhibitor of thymidylate synthase, CB3717, on human lymphoblastoid cells
8. Biochemical and cellular pharmacology of 1843U89, a novel benzoquinazoline inhibitor of thymidylate synthase
9. Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs
10. Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay
11. Initial phase I evaluation of the novel thymidylate synthase inhibitor LY231514, using the modified continual reassessment method for dose escalation
12. A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate
13. Crystal structure of human thymidylate synthase: A structural mechanism for guiding substrates into the active site
14. Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug
15. Studies on engineering crystallizability by mutation of surface residues of human thymidylate synthase
16. Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase
17. The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design
18. Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folate
19. Crystal structure of Escherichia coli thymidylate synthase containing bound 5-fluoro-2′-deoxyuridylate and 10-propargyl-5,8-dideazafolate
20. Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: Assessing specificity and affinity
21. Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug
22. Structural basis for recognition of polyglutamyl folates by thymidylate synthase
23. Creation and characterization of 5-fluorodeoxyuridine-resistant Arg50 loop mutants of human thymidylate synthase
24. Replacement set mutagenesis of the four phosphate-binding arginine residues of thymidylate synthase
25. Energetic contributions of four arginines to phosphate-binding in thymidylate synthase are more than additive and depend on optimization of "effective charge balance"
26. Probing the folate-binding site of human thymidylate synthase by site-directed mutagenesis. Generation of mutants that confer resistance to raltitrexed, Thymitaq, and BW1843U89
27. Random sequence mutagenesis and resistance to 5-fluorouridine in human thymidylate synthases
28. Tolerance of 5-fluorodeoxyuridine resistant human thymidylate synthases to alterations in active site residues
29. Catalytic role of histidine 147 in Escherichia coli thymidylate synthase
30. Mechanisms of acquired resistance to thymidylate synthase inhibitors: The role of enzyme stability
31. A hydroxyl group at residue 216 is essential for catalysis by human thymidylate synthase
32. Substitution at residue 214 of human thymidylate synthase alters nucleotide binding and isomerization of ligand-protein complexes
33. Contributions of orientation and hydrogen bonding to catalysis in Asn229 mutants of thymidylate synthase
34. The separate effects of E60Q in L. casei thymidylate synthase delineate between mechanisms for formation of intermediates in catalysis
35. D221 in thymidylate synthase controls conformation change, and thereby opening of the imidazolidine
36. Use of strain in a stereospecific catalytic mechanism: Crystal structures of Escherichia coli thymidylate synthase bound to FdUMP and methylenetetrahydrofolate
37. Improving enzymes for cancer gene therapy
38. Hydrogen bonding and biological specificity analysed by protein engineering
39. Expression of human thymidylate synthase in Escherichia coli
40. Site-directed mutagenesis of virtually any plasmid by eliminating a unique site
41. Direct spectrophotometric evidence for the oxidation of tetrahydrofolate during the enzymatic assay
42. Processing of X-ray diffraction data collected in oscillation mode
43. Crystallography and NMR system: A new software suite for macromolecular structure determination
44. Assessment of phase accuracy by cross validation - The free R-value - Methods and applications
45. Crystallographic refinement by simulated annealing. Application to a 2.8 Å resolution structure of aspartate aminotransferase
46. AMoRe - An automated package for molecular replacement
47. Improved methods for building protein models in electron density maps and the location of errors in these models
48. An essential role for water in an enzyme reaction mechanism: The crystal structure of the thymidylate synthase mutant E58Q
49. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities
50. MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures
51. Raster3D: Photorealistic molecular graphics
52. Ligplot - A program to generate schematic diagrams of protein ligand interactions