Claims
- 1. A compound that abrogates the cell cycle G2 checkpoint when administered to a cell, wherein the compound has following structure:
- 2. A compound of claim 1, wherein the compound abrogates the DNA-damage-induced G2 checkpoint when administered to a cell.
- 3. A compound of claim 2, wherein the compound suppresses or kills DNA-damaged cells when administered to a population of cells comprising normal cells and DNA-damaged cells.
- 4. A compound of claim 2, wherein the compound sensitizes a cell to a DNA-damaging agent or treatment when administered to a cell.
- 5. A compound of claim 1, comprising at least one compound selected from: 4-chloro-benzoic acid 4-methoxy-phenyl ester (CDBC004); 4-chloro-benzoic acid p-tolyl ester (CBDC401); 4-bromo-benzoic acid p-tolyl ester (CBDC402); 3,4,5-trifluoro-benzoic acid p-toly I ester (CBDC403); 4-fluoro-benzoic acid 4-bromo-pheny 1 ester (CBDC404); 3,4-dichloro-benzoic acid p-tolyl ester (CBDC405); 2,4-dichloro-benzoic acid p-tolyl ester (CBDC406); 4-fluoro-benzoic acid p-tolyl ester (CBDC407);2,3,4,5,6-pentafluoro-benzoic acid p-tolyl ester (CBDC408); 4-chloro-benzoic acid 3,4-dimethyl-phenyl ester (CBDC409);4-chloro-benzoic acid 4-hydroxy-phenyl ester (CBDC410); 4-fluoro-benzoic acid 4-hydroxy-phenyl ester (CBDC411) 4-bromo-benzoic acid 4-fluoro-phenyl ester (CBDC412); 4-bromo-benzoic acid 4-trifluoromethyl-phenyl ester (CBDC413); 4-bromo-benzoic acid 4-hydroxy-phenyl ester (CBDC414); 4-bromo-benzoic acid 4-trifluoromethoxy-phenyl ester (CBDC415); 4-Bromo-benzoic acid 6-methyl-pyridin-3-yl ester (CBDC418); 4-bromo-thiobenzoic acid 0-p-tolyl ester (CBDC440); 4-bromo-dithiobenzoic acid p-tolyl ester (CBDC441); 4-bromo-thiobenzoic acid S-p-tolyl ester (CBDC442).
- 6. A composition of claim 1, comprising 4-chloro-benzoic acid 4-methoxy-phenyl ester (CBDC004) having the structure:
- 7. A composition of claim 1, comprising 4-chloro-benzoic acid p-tolyl ester (CBDC401) having the structure:
- 8. A composition of claim 1, comprising 4-bromo-benzoic acid p-tolyl ester (CBDC402) having the structure:
- 9. A composition of claim 1, comprising 3,4,5-trifluoro-benzoic acid p-tolyl ester (CBDC402) having the structure:
- 10. A composition of claim 1, comprising 4-fluoro-benzoic acid 4-bromo-phenyl ester (CBDC404) having the structure:
- 11. A composition of claim 1, comprising 3,4-dichloro-benzoic acid p-tolyl ester (CBDC405) having the structure:
- 12. A composition of claim 1, comprising 2,4-dichloro-benzoic acid p-tolyl ester (CBDC406) having the structure:
- 13. A composition of claim 1, comprising 4-fluoro-benzoic acid p-tolyl ester (CBDC407) having the structure:
- 14. A composition of claim 1, comprising 2,3,4,5,6-pentafluoro-benzoic acid p-tolyl ester (CBDC408) having the structure:
- 15. A composition of claim 1, comprising 4-chloro-benzoic acid 3,4-dimethyl-phenyl ester (CBDC409) having the structure:
- 16. A composition of claim 1, comprising 4-chloro-benzoic acid 4-hydroxy-phenyl ester (CBDC410) having the structure:
- 17. A composition of claim 1, comprising 4-fluoro-benzoic acid 4-hydroxy-phenyl ester (CBDC411) having the structure:
- 18. A composition of claim 1, comprising 4-bromo-benzoic acid 4-fluoro-phenyl ester (CBDC412) having the structure:
- 19. A composition of claim 1, comprising 4-bromo-benzoic acid 4-trifluoromethyl-phenyl ester (CBDC413) having the structure:
- 20. A composition of claim 1, comprising 4-bromo-benzoic acid 4-hydroxy-phenyl ester (CBDC414) having the structure:
- 21. A composition of claim 1, comprising 4-bromo-benzoic acid 4-trifluoromethoxy-phenyl ester (CBDC415) having the structure:
- 22. A composition of claim 1, comprising 4-bromo-benzoic acid 6-methyl-pyridin-3-yl ester (CBDC418) having the structure:
- 23. A composition of claim 1, comprising 4-bromo-thiobenzoic acid 0-p-tolyl ester (CBDC440) having the structure:
- 24. A composition of claim 1, comprising 4-bromo-dithiobenzoic acid p-tolyl ester (CBDC441) having the structure:
- 25. A composition of claim 1, comprising 4-bromo-thiobenzoic acid S-p-tolyl ester (CBDC442) having the structure:
- 26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a composition of claim 1.
- 27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a composition of claim 2.
- 28. A method of abrogating the G2 checkpoint in a cell, comprising administering to a cell at least one compound of claim 1 in an amount effective to inhibit the G2 checkpoint.
- 29. A method for killing or suppressing a cell having a proliferative disorder comprising, administering to at least one cell having a proliferative disorder a compound of claim 1 in an amount effective to inhibit the G2 checkpoint.
- 30. A method of treating a condition characterized by a proliferative or differentiative disorder comprising, administering at least one compound of claim 1 in an amount effective to treat the disorder.
- 31. A method of selectively suppressing or killing DNA-damaged cells comprising, administering a compound of claim 2 in an amount effective to inhibit the DNA-damage-induced G2 checkpoint, to a population of cells comprising normal cells and DNA-damaged cells.
- 32. The method of claim 31, wherein the DNA-damaged cells are cancer cells.
- 33. The method of claim 31, wherein the DNA-damnaged cells are xenograft tumor cells.
- 34. The method of claim 31, wherein administering a compound of claim 2 sensitizes the DNA-damaged cells to a DNA-damaging agent or treatment.
- 35. The method of claim 34, wherein the DNA-damaged cells are cancer cells, and further wherein administering a compound of claim 2 sensitizes the cancer cells to a DNA-damaging agent or treatment.
- 36. A method of screening for non-peptide compounds that abrogate the DNA-damage-induced G2 checkpoint comprising:
(a) providing a test compound; (b) providing a population of cells; (c) administering to the population of cells a DNA-damaging agent that causes accumulation of G2/M phase cells; (d) administering the test compound to a first treated portion of the population treated with the DNA-damaging agent; (e) measuring the number of cells in G2/M phase in the first treated portion of the population, wherein measuring the number of cells in G2/M phase in the population indicates the number of cells in G2 cell cycle arrest; (f) measuring the number of cells in G2/M phase in a second untreated portion of the population treated with the DNA-damaging agent, wherein measuring the number of cells in G2/M phase in the population indicates the number of cells in G2 cell cycle arrest; and (g) comparing the number in (e) with the number in (f), wherein a lower number of cells in G2/M phase in step (e) indicates that the test compound abrogated the DNA-damage-induced G2 cell cycle checkpoint in the first treated portion.
- 37. The method of claim 40, wherein the compound is a compound of claim 1.
- 38. The method of claim 42, wherein the compound is a compound of claim 2.
- 39. A compound that abrogates the cell cycle G2 checkpoint when administered to a cell, wherein the compound has following structure:
- 40. A compound of claim 39, wherein the compound abrogates the DNA-damage-induced G2 checkpoint when administered to a cell.
- 41. A compound of claim 40, wherein the compound suppresses or kills DNA-damaged cells when administered to a population of cells comprising normal cells and DNA-damaged cells.
- 42. A compound of claim 40, wherein the compound sensitizes a cell to a DNA-damaging agent or treatment when administered to a cell.
- 43. A method of abrogating the G2 checkpoint in a cell, comprising administering to a cell at least one compound of claim 39 in an amount effective to inhibit the G2 checkpoint.
- 44. A method for killing or suppressing a cell having a proliferative disorder comprising, administering to at least one cell having a proliferative disorder a compound of claim 39 in an amount effective to inhibit the G2 checkpoint.
- 45. A method of treating a condition characterized by a proliferative or differentiative disorder comprising, administering at least one compound of claim 39 in an amount effective to treat the disorder.
- 46. A method of selectively suppressing or killing DNA-damaged cells comprising, administering a compound of claim 40 in an amount effective to inhibit the DNA-damage-induced G2 checkpoint, to a population of cells comprising normal cells and DNA-damaged cells.
- 47. The method of claim 46, wherein the DNA-damaged cells are cancer cells.
- 48. The method of claim 46, wherein the DNA-damaged cells are xenograft tumor cells.
- 49. The method of claim 46, wherein administering a compound of claim 40 sensitizes the DNA-damaged cells to a DNA-damaging agent or treatment.
- 50. The method of claim 49, wherein the DNA-damaged cells are cancer cells, and further wherein administering a compound of claim 40 sensitizes the cancer cells to a DNA-damaging agent or treatment.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. application Serial No. 60/386,930, filed Jun. 6, 2002.
Provisional Applications (1)
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Number |
Date |
Country |
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60386930 |
Jun 2002 |
US |