Methods for modulating function of proliferating cell nuclear antigen (PCNA) and treating cancer with PCNA-targeting compounds
Pharmaceutical compositions and methods for inhibiting cell growth, modulating function of PCNA, treating prostate cancer, and enhancing PCNA trimer formation are disclosed. The methods include administering an effective amount of a compound of Formula (I): (a representative image), or an effective amount of a specific compound of Formula (II): (a representative image).
1. A method for inhibiting growth of a cell, the method comprising contacting the cell with an effective amount of a compound structurally depicted as,
wherein:
X is
R1 is
each R 4 is independently selected from the group consisting of H, halo, cyano, hydroxyl, and methyl;
R 2 is
and tautomers thereof, with the proviso that
at least one R 4 is not H, and R 4 on R 1 is neither ortho-halo nor methyl; and
wherein the compound is provided in a concentration of from about 0.1 to about 10 μM, and the growth of the cell is inhibited by up to about 100%.
2. The method according to claim 1 , wherein the growth of the cell is inhibited by about 50%.
3. The method according to claim 1 , wherein contacting the cell with the compound induces apoptosis of the cell.
4. The method according to claim 1 , wherein the cell is a mammalian cell selected from the group consisting of a human cell, a non-human primate cell, a canine cell, a feline cell, a murine cell, a bovine cell, an equine cell, a porcine cell, and a lagomorph cell.
5. The method according to claim 1 , wherein the cell is selected from the group consisting of a tumor cell and normal cell, and wherein:
the tumor cell is selected from the group consisting of a breast cancer cell, a prostate cancer cell, a colon cancer cell, a cervical cancer cell, a melanoma cell, a multidrug resistant colon cancer cell, and a fibrosarcoma cell, and
the normal cell is selected from the group consisting of a blood vessel endothelial cell, a bone marrow mesenchymal stem cell, a mammary epithelial cell, a prostate epithelial cell, a spleen lymphocyte, a lung endothelial cell, and a prostate endothelial cell.
6. The method according to claim 1 , wherein the compound is selected from the group consisting of:
7. The method according to claim 1 , further comprising contacting the cell with an effective amount of cisplatin.
8. A method for treating prostate cancer in a subject in need thereof, the method comprising administering an effective amount of a compound to the subject, wherein the compound is depicted structurally as,
wherein:
X is
R1 is
each R 4 is independently selected from the group consisting of H, halo, cyano, hydroxyl, and methyl;
R 2 is
and tautomers thereof, with the proviso that
at least one R 4 is not H, and R 4 on R 1 is neither ortho-halo nor methyl; and
wherein the compound is administered in a dose of about 10 to about 50 μg/g.
9. The method according to claim 8 , wherein growth of a prostate tumor is reduced.
10. The method according to claim 9 , wherein volume of the prostate tumor is reduced by from about 70% to about 90%.
11. The method according to claim 10 , wherein the volume of the prostate tumor is reduced by from about 70% to about 85%.
12. The method according to claim 8 , wherein a prostate tumor is eradicated.
13. The method according to claim 8 , wherein the compound is administered in a dose of about 10 μg/g every other day.
14. The method according to claim 13 , wherein the dose of the compound is systemically administered about three times per week.
15. The method according to claim 8 , wherein the subject is a mammal.
16. The method according to claim 15 , wherein the mammal is human.
17. The method according to claim 8 , wherein the compound is selected from the group consisting of:
18. A method for inhibiting growth of a cell, the method comprising:
contacting the cell with an effective amount of cisplatin; and
contacting the cell with an effective amount of a compound structurally depicted as,
wherein:
X is
R1 is
each R 4 is independently selected from the group consisting of H, halo, cyano, hydroxyl,
R 2 is
and tautomers thereof, with the proviso that
at least one R 4 is not H, and R 4 on R 1 is neither ortho-halo nor methyl.
19. The method according to claim 18 , wherein the growth of the cell is inhibited by up to about 100%.
20. The method according to claim 18 , wherein the growth of the cell is inhibited by about 50%.
21. The method according to claim 18 , wherein the compound is provided in a concentration of from about 0.1 to about 10 μM.
22. The method according to claim 18 , wherein contacting the cell with the compound induces apoptosis of the cell.
23. The method according to claim 18 , wherein the cell is a mammalian cell selected from the group consisting of a human cell, a non-human primate cell, a canine cell, a feline cell, a murine cell, a bovine cell, an equine cell, a porcine cell, and a lagomorph cell.
24. The method according to claim 18 , wherein the cell is selected from the group consisting of a tumor cell and normal cell, and wherein:
the tumor cell is selected from the group consisting of a breast cancer cell, a prostate cancer cell, a colon cancer cell, a cervical cancer cell, a melanoma cell, a multidrug resistant colon cancer cell, and a fibrosarcoma cell, and
the normal cell is selected from the group consisting of a blood vessel endothelial cell, a bone marrow mesenchymal stem cell, a mammary epithelial cell, a prostate epithelial cell, a spleen lymphocyte, a lung endothelial cell, and a prostate endothelial cell.
25. The method according to claim 18 , wherein the compound is selected from the group consisting of:
26. A method for treating prostate cancer in a subject in need thereof, the method comprising administering an effective amount of a compound to the subject, wherein the compound is selected from the group consisting of:
27. The method according to claim 26 , wherein the compound is administered in a dose of about 10 to about 50 μg/g.
28. The method according to claim 27 , wherein the compound is administered in a dose of about 10 μg/g every other day.
29. The method according to claim 27 , wherein the dose of the compound is systemically administered about three times per week.
30. The method according to claim 26 , wherein the subject is a mammal.
31. The method according to claim 30 , wherein the mammal is human.