Singleton inhibitors of sumoylation enzymes and methods for their use
According to the embodiments described herein, a SUMOylation inhibitor compound comprising a singleton scaffold is provided. In some embodiments, a method for inhibiting a SUMOylation enzyme in a cell is provided. Such a method may include administering a SUMOylation inhibitor compound to the cell. In some aspects, the SUMOylation enzyme is SUMO E1 or SUMO E2. In some aspects, the method may be used to inhibit a cancer cell in vitro (e.g., grown in culture) or in vivo (e.g., as part of a tumor in a subject). In other embodiments, a method for treating a cancer, degenerative diseases and viral infection is provided. Such a method may include administering an effective amount of a pharmaceutical composition to a subject having the cancer. The pharmaceutical composition may include a singleton SUMOylation inhibitor compound. In some embodiments, the method for treating a cancer may further comprise administering one or more DNA-damaging therapy in combination with administration of the pharmaceutical composition.
1. A SUMOylation inhibitor compound comprising the structure
Or a pharmaceutically acceptable solvate, salt and stereoisomer thereof, including mixtures thereof in all ratios, wherein:
A is O, S, NR 7 where R 7 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, benzyl, alkyl-aryl where R 7 is optionally substituted with one to four R 8 groups, CH 2 , CH 2 CH 2 , CH═CH;
B is O, S, NR 11 where R 11 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, benzyl, alkyl-aryl where R 11 is optionally substituted with one to four R 8 groups;
R 1 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 1 is optionally substituted with one to four R 8 groups;
R 2 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 2 is optionally substituted with one to four R 8 groups;
R 3 is —C(O)—OR 9 , ON, —C(O)—NHR 9 , —C(O)—N(R 9 ) 2 , —SO 2 R 9 and R 9 is H, alkyl, haloalkyl, aryl, heteroaryl where R 9 is optionally substituted with one to four R 8 groups;
R 4 is —C(O)—OR 9 , ON, —C(O)—NHR 9 , —C(O)—N(R 9 ) 2 , —SO 2 R 9 and R 9 is H, alkyl, haloalkyl, aryl, heteroaryl where R 9 is optionally substituted with one to four R 8 groups;
R 5 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 5 is optionally substituted with one to four R 8 groups;
R 6 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 6 is optionally substituted with one to four R 8 groups; and
R 8 : is halo, —OR 10 , —N(R 10 ) 2 , —SR 10 , —SO 2 R 10 , —S(O 2 )N(R 10 ) 2 , —S(O) 2 OR 10 , —N(R 10 )S(O) 2 R 10 , —OS(O) 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)R 10 , —OC(O)OR 10 , —OC(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)OR 10 , —N(R 10 )C(O)N(R 10 ) 2 , —ON, —NO 2 , alkyl, haloalkyl, alkyl-OR 10 , or alkyl-N(R 10 ) 2 ,
where each R 10 is independently of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or
and pharmaceutically acceptable solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein:
wherein R 1 , R 2 , R 3 and R 4 are selected from the group consisting of H, and —C(O)—O—R 7 ;
wherein X 1 and X 2 are selected from the group consisting of C, N, O, S, and P;
wherein R 5 and R 6 are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and heteroaryl; and
wherein R 7 is alkyl.
2. The compound of claim 1 , wherein the structure of the compound comprises
wherein R 1 is selected from CH 2 Ph, CH 2 C 6 H 4 Me, CH 2 C 6 H 4 OMe, CH 2 C 6 H 4 F, CH 2 C 6 H 4 OF 3 n-Pr, Allyl, Vinyl or Me; and
wherein R 2 is selected from H, Cl, Me or OMe.
3. The compound of claim 2 , wherein the compound is selected from the group having the structure of:
4. The compound of claim 2 , wherein the compound is
5. The compound of claim 2 , wherein the compound is
6. A method for inhibiting a SUMOylation enzyme in a cell, comprising administering an effective amount of a SUMOylation inhibitor compound to the cell, the compound comprising a structure:
Or a pharmaceutically acceptable solvate, salt and stereoisomer thereof, including mixtures thereof in all ratios, wherein:
A is O, S, NR 7 where R 7 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, benzyl, alkyl-aryl where R 7 is optionally substituted with one to four R 8 groups, CH 2 , CH 2 CH 2 , CH═CH;
B is O, S, NR 11 where R 11 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, benzyl, alkyl-aryl where R 11 is optionally substituted with one to four R 8 groups;
R 1 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 1 is optionally substituted with one to four R 8 groups;
R 2 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 2 is optionally substituted with one to four R 8 groups;
R 3 is —C(O)—OR 9 , CN, —C(O)—NHR 9 , —C(O)—N(R 9 ) 2 , —SO 2 R 9 and R 9 is H, alkyl, haloalkyl, aryl, heteroaryl where R 9 is optionally substituted with one to four R 8 groups;
R 4 is —C(O)—OR 9 , CN, —C(O)—NHR 9 , —C(O)—N(R 9 ) 2 , —SO 2 R 9 and R 9 is H, alkyl, haloalkyl, aryl, heteroaryl where R 9 is optionally substituted with one to four R 8 groups;
R 5 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 5 is optionally substituted with one to four R 8 groups;
R 6 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 6 is optionally substituted with one to four R 8 groups; and
R 8 : is halo, —OR 10 , —N(R 10 ) 2 , —SR 10 , —SO 2 R 10 , —S(O 2 )N(R 10 ) 2 , —S(O) 2 OR 10 , —N(R 10 )S(O) 2 R 10 , —OS(O) 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)R 10 , —OC(O)OR 10 , —OC(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)OR 10 , —N(R 10 )C(O)N(R 10 ) 2 , —CN, —NO 2 , alkyl, haloalkyl, alkyl-OR 10 , or alkyl-N(R 10 ) 2 ,
where each R 10 is independently of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or
and pharmaceutically acceptable solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein:
wherein R 1 , R 2 , R 3 and R 4 are selected from the group consisting of H, and —C(O)—O—R 7 ;
wherein X 1 and X 2 are selected from the group consisting of C, N, O, S, and P;
wherein R 5 and R 6 are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and heteroaryl; and
wherein R 7 is alkyl.
7. The method of claim 6 , wherein the structure of the compound comprises
wherein R 1 is selected from CH 2 Ph, CH 2 C 6 H 4 Me, CH 2 C 6 H 4 OMe, CH 2 C 6 H 4 F, CH 2 C 6 H 4 OF 3 n-Pr, Allyl, Vinyl or Me; and
wherein R 2 is selected from H, Cl, Me or OMe.
8. The method of claim 7 , wherein the compound is selected from the group having the structure of:
9. The method of claim 7 , wherein the compound is
10. The method of claim 7 , wherein the compound is
11. The method of claim 6 , wherein the SUMOylation enzyme is SUMO E1 or SUMO E2.
12. The method of claim 6 , wherein the cell is part of an in vivo population of cells in a subject.
13. The method of claim 12 , wherein the population of cells is a tumor, a population of virally infected cells, a population of cells associated with heart disease, a population of cells associated with a degenerative disease, or a population of cells associated with a genetic disease.
14. The method of claim 6 , wherein the cell is part of a population of cells grown in culture.
15. The method of claim 14 , wherein the cell is part of a primary cell line, a secondary cell line or an immortal cell line.
16. The method of claim 15 , wherein the cell line is derived from a tumor, a degenerative disease, a genetic disease or a cardiovascular disease.
17. A method for treating a disease comprising administering an effective amount of a pharmaceutical composition to a subject having the disease, the pharmaceutical composition comprising a compound comprising the structure:
Or a pharmaceutically acceptable solvate, salt and stereoisomer thereof, including mixtures thereof in all ratios, wherein:
A is O, S, NR 7 where R 7 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, benzyl, alkyl-aryl where R 7 is optionally substituted with one to four R 8 groups, CH 2 , CH 2 CH 2 , CH═CH;
B is O, S, NR 11 where R 11 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, benzyl, alkyl-aryl where R 11 is optionally substituted with one to four R 8 groups;
R 1 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 1 is optionally substituted with one to four R 8 groups;
R 2 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 2 is optionally substituted with one to four R 8 groups;
R 3 is —C(O)—OR 9 , CN, —C(O)—NHR 9 , —C(O)—N(R 9 ) 2 , —SO 2 R 9 and R 9 is H, alkyl, haloalkyl, aryl, heteroaryl where R 9 is optionally substituted with one to four R 8 groups;
R 4 is —C(O)—OR 9 , CN, —C(O)—NHR 9 , —C(O)—N(R 9 ) 2 , —SO 2 R 9 and R 9 is H, alkyl, haloalkyl, aryl, heteroaryl where R 9 is optionally substituted with one to four R 8 groups;
R 5 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 5 is optionally substituted with one to four R 8 groups;
R 6 is H, alkyl, haloalkyl, alcoxyalkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, benzyl, alkyl-aryl where R 6 is optionally substituted with one to four R 8 groups; and
R 8 : is halo, —OR 10 , —N(R 10 ) 2 , —SR 10 , —SO 2 R 10 , —S(O 2 )N(R 10 ) 2 , —S(O) 2 OR 10 , —N(R 10 )S(O) 2 R 10 , —OS(O) 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —OC(O)R 10 , —OC(O)OR 10 , —OC(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)OR 10 , —N(R 10 )C(O)N(R 10 ) 2 , —CN, —NO 2 , alkyl, haloalkyl, alkyl-OR 10 , or alkyl-N(R 10 ) 2 ,
where each R 10 is independently of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or
and pharmaceutically acceptable solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein:
wherein R 1 , R 2 , R 3 and R 4 are selected from the group consisting of H, and —C(O)—O—R 7 ;
wherein X 1 and X 2 are selected from the group consisting of C, N, O, S, and P;
wherein R 5 and R 6 are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and heteroaryl;
wherein R 7 is alkyl; and
wherein said disease is selected from colorectal cancer, pancreatic cancer, bone cancer or breast cancer.
18. The method of claim 17 , wherein the structure of the compound comprises
wherein R 1 is selected from CH 2 Ph, CH 2 C 6 H 4 Me, CH 2 C 6 H 4 OMe, CH 2 C 6 H 4 F, CH 2 C 6 H 4 OF 3 n-Pr, Allyl, Vinyl or Me; and
wherein R 2 is selected from H, Cl, Me or OMe.
19. The method of claim 18 , wherein the compound is selected from the group having the structure of: