Oligo-benzamide compounds and their use in treating cancers
View Patent ↗The present invention includes bis- and tris-benzamide compounds that block AR signaling and have activity against prostate cancer. Uses for these compounds, and pharmaceutical compositions containing the same, also are provided.
1. A compound of formula (I or II):
wherein:
R 1 , R 2 and R 3 are each independently H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 1 -C 15 optionally substituted arylalkyl, —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRR′, —(CH 2 ) n —NH(C═NH)NRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —OR, —(CH 2 ) n —SR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group or
wherein R is independently a H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 1-15 optionally substituted arylalkyl, hydroxyl, C 1-10 alkoxy, amino, C 1-10 monoalkylamino, C 1-10 dialkylamino, guanidine, nitro, carboxylic acid, C 1-10 alkylcarbonyl, C 1-15 arylcarbonyl, halogen, sulfhydryl, C 1-10 alkylsulfenyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfonyl, sulfonic acid, sulfate, phosphenyl, phosphinyl, phosphonic acid, phosphate group;
X is
Y is —(CH 2 ) n COOR 4 , —(CH 2 ) n CONR 4 R 5 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n —NR 4 R 5 , —(CH 2 ) n —NH(C═NH)NR 4 R 5 , —(CH 2 ) n —NR 4 COR 5 , —(CH 2 ) n —NR 4 COOR 5 ,—(CH 2 )—NR 4 CONR 5 , —(CH 2 ) n —OR 4 , —(CH 2 ) n —SR 4 , —(CH 2 ) n —SO m R 4 , —(CH 2 ) n —PO m R 4 , wherein n and m may be any number between 0 and 6,
R 4 and R 5 are independently selected from —H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl,C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group; and A, A′ and A″ are independently —O—, —S—, —NR—, —(CH 2 ) n —, —CO— wherein n may be any number between 1-6.
2. The compound of claim 1 , wherein Y is —C(O)NH 2 .
3. The compound of claim 1 , wherein A, A′ and A″ are each O.
4. The compound of claim 1 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl, C 1-10 hydroxyalkyl, C 1-10 alkenyl or C 1 -C 15 arylalkyl.
5. The compound of claim 3 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl, C 1-10 hydroxyalkyl, C 1-10 alkenyl or C 1 -C 15 arylalkyl.
6. The compound of claim 1 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl or C 1-10 hydroxyalkyl.
7. The compound of claim 3 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl or C 1-10 hydroxyalkyl.
8. The compound of claim 1 , wherein Y is COOCH 3 .
9. The compound of claim 1 , wherein A, A′ and A″ are each NH.
10. The compound of claim 8 , wherein A, A′ and A″ are each NH.
11. The compound of claim 8 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl, C 1-10 hydroxyalkyl, C 1-10 alkenyl or C 1 -C 15 arylalkyl.
12. The compound of claim 10 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl or C 1-10 hydroxyalkyl.
13. The compound of claim 1 , having the formula selected from:
14. A method of inhibiting a prostate tumor cell in a subject comprising administering to said subject a therapeutically sufficient amount of an oligo-benzamide peptidomimetic compound as shown in claim 1 .
15. The method of claim 14 , wherein the prostate tumor cell is an androgen receptor (AR)- or estrogen receptor (ER)-positive tumor cell.
16. The method of claim 14 , prostate tumor cell is a carcinoma cell.
17. The method of claim 14 , wherein administering comprises local, regional, systemic, or continual administration.
18. The method of claim 14 , wherein said peptidomimetic compound is fused to a cell delivery domain.
19. The method of claim 14 , wherein inhibiting comprises inducing growth arrest of said prostate tumor cell, apoptosis of said prostate tumor cell and/or necrosis of a prostate tumor tissue comprising said prostate tumor cell.
20. The method of claim 14 , further comprising providing to said subject a second anti-cancer therapy.
21. The method of claim 20 , wherein said second anti-cancer therapy is surgery, chemotherapy, radiotherapy, hormonal therapy, toxin therapy, immunotherapy, and cryotherapy.
22. The method of claim 20 , wherein said second anti-cancer therapy is provided prior to administering said compound.
23. The method of claim 20 , wherein said second anti-cancer therapy is provided after administering said compound.
24. The method of claim 20 , wherein said second anti-cancer therapy is provided at the same time as said compound.
25. The method of claim 14 , wherein said subject is a human.
26. The method of claim 14 , wherein said compound is administered at about 0.1 to about 100 mg/kg.
27. The method of claim 26 , wherein said compound is administered at about 1 to about 50 mg/kg.
28. The method of claim 14 , wherein said compound is administered daily.
29. The method of claim 14 , further comprising assessing AR- or ER-driven gene expression in said prostate tumor cell of said subject after administering said compound.
30. A pharmaceutical composition comprising a compound as shown in claim 1 , dispersed in a pharmaceutically acceptable carrier, buffer or diluent.
31. The method of claim 28 , wherein said compound is administered daily for 7 days, 2 weeks, 3 weeks, 4 weeks, one month, 6 weeks, 8 weeks, two months, 12 weeks, or 3 months.
32. The method of claim 14 , wherein said compound is administered weekly.
33. The method of claim 32 , wherein said compound is administered weekly for 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks.
34. The method of claim 14 , further comprising assessing AR- or ER-driven gene expression in said prostate tumor cell of said subject prior to administering said compound.