Small molecule inhibitors of MUC1 and methods of identifying the same
The invention provides methods for the identification of small molecules that inhibit MUC1 oligomerization, and the functions flowing therefrom. In addition, small molecules that prevent MUC1 oligomerization are disclosed. Identified molecules will find use in treating a variety of MUC1-related inflammatory conditions, including MUC1-related cancers.
1. A method of inhibiting inflammatory signaling in a cancer cell comprising:
(a) assessing MUC1 overexpression in said cancer cell, and;
(h) further contacting said cancer cell with a flavone having the structure of:
or a salt thereof, wherein
R 1 is H, —OH, ═O, substituted or unsubstituted alkyl(C 1-8 ), alkoxy(C 1-8 ), haloalkyl(C 1-8 ), substituted phenyl or unsubstituted phenyl, wherein if R 1 is ═O, C 7 -C 8 is a double bond;
R 2 is H, —OH, alkyl(C 1-8 ), substituted phenyl, unsubstituted phenyl, phenyl, phenyl thiazole, imidazole, pyrazole or furan;
R 3 is H, —OH, ═O, halogen, haloalkyl(C 1-8 ), substituted or unsubstituted alkyl(C 1-8 ), substituted phenyl or unsubstituted phenyl, wherein if R 3 is ═O, C 8 -C 9 is a double bond;
R 4 is H or —OH;
R 5 is H, —OH, substituted or unsubstituted alkyl(C 1-8 ) or alkoxy(C 1-8 ), or OR 8 , wherein R 8 is alkyl(C 1-8 ), an ester or an amide;
R 6 is H, —OH substituted or unsubstituted alkyl(C 1-8 ) or alkoxy(C 1-8 ), or OR 8 , wherein R 8 is alkyl(C 1-8 ), an ester or an amide; and
R 7 is H, —OH, or substituted or unsubstituted alkyl(C 1-8 ),
with the proviso that R 1 and R 3 cannot both be ═O.
2. The method of claim 1 , wherein said flavone in Morin or a salt thereof.
3. The method of claim 1 , wherein said flavone is Apigenin or Kaempterol or a salt thereof.
4. The method of claim 1 , wherein said flavone in Fisetin or a salt thereof.
5. The method of claim 1 , wherein said flavone in PD98059 or a salt thereof.
6. The method of claim 1 , wherein said flavone is 7-(benzyloxy)-4-(trifluoromethyl)-2H-chromen-2-one.
7. The method of claim 1 , wherein said flavone is 7-[(3-oxobutan-2-yl)oxy]-4-phenyl-2H-chromen-2-one.
8. The method of claim 1 , wherein said R 1 is ═O.
9. The method of claim 1 , wherein said R 3 is ═O.
10. The method of claim 1 , wherein the cancer cell is a solid tumor cell.
11. The method of claim 10 , wherein the solid tumor cell is a lung cancer cell, a brain cancer cell, a head & neck cancer cell, a breast cancer cell, a skin cancer cell, a liver cancer cell, a pancreatic cancer cell, a stomach cancer cell, a colon cancer cell, a rectal cancer cell, a uterine cancer cell, a cervical cancer cell, an ovarian cancer cell, a testicular cancer cell, a skin cancer cell or a esophageal cancer cell.
12. The method of claim 1 , wherein the MUC1 positive cancer cell is a leukemia or myeloma cell.
13. The method of claim 12 , wherein the MUC-1 positive cancer cell is an acute myeloid leukemia, chronic myelogenous leukemia or multiple myeloma.
14. The method of claim 1 , wherein the cancer cell is located in a subject.
15. The method of claim 14 , wherein said subject is a human subject.
16. The method of claim 14 , further comprising administering to said subject a second cancer therapy.
17. The method of claim 16 , wherein said second cancer therapy is chemotherapy, radiotherapy, immunotherapy, toxin therapy, hormone therapy, gene therapy or surgery.
18. The method of claim 16 , wherein said second therapy is given at the same time as said flavone.
19. The method of claim 16 , wherein said second therapy is given before or after said flavone.
20. The method of claim 1 , further comprising contacting said cell with a second anti-inflammatory agent.
21. The method of claim 20 , wherein said second anti-inflammatory agent is contacted prior to or after said compound.
22. The method of claim 20 , wherein said second anti-inflammatory agent is contacted at the same time as said compound.