Inhibition of small ubiquitin-like modifier enzymes with substituted pyrrolo[2,3-b]quinoxalines
According to the embodiments described herein, a methods for inhibiting small ubiquitin-like modifier enzymes in a cell are provided. Such methods may include administering certain substituted pyrrolo[2,3-b]-quinoxalines to the cell. In some aspects, the small ubiquitin-like modifier enzyme is SUMO E1 or SUMO E2. In some aspects, the methods 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, methods for treating a cancer, degenerative diseases and viral infection are provided. Such methods may include administering an effective amount of a pharmaceutical composition to a subject having cancer. The pharmaceutical composition may include a small ubiquitin-like modifier inhibitor compound. In some embodiments, the method for treating a disease may further comprise administering one or more DNA-damaging therapy in combination with administration of the pharmaceutical composition.
1. A method for inhibiting a small ubiquitin-like modifier enzyme in a cell, comprising administering to the cell a compound having the structure:
and pharmaceutically acceptable salts and stereoisomers thereof;
wherein R 1 and R 2 are independently selected from the group consisting of H, —S(O) 2 —R 8 , —CN and —C(O)—X—R 9 ;
wherein R 8 is an alkyl, or aryl;
wherein R 9 is an alkyl, aryl, or heteroaryl;
wherein X is selected from the group consisting of CH 2 , O, NH, and S;
wherein R 3 is selected from the group consisting of an alkyl, an alkenyl, and an alkylaryl;
wherein each of R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, a halogen, and an alkyl;
wherein X 1 is selected from the group consisting of CH 2 , NH, O, and S; and
wherein X 2 , X 3 and X 4 are N; or
and pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein:
A and B are N;
R 1 is H, alkyl, haloalkyl, alkyl-OR 1 , aryl, heterocyclyl, benzyl, or alkyl-aryl where R 1 is optionally substituted with one to four R 4 groups;
R 2 is H or L-R 5 , wherein L is —C(O)— or —S(O) 2 —, and R 5 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, benzyl, or alkyl-aryl optionally substituted with one to four R 4 groups;
R 3 is CN, —C(O)—OR 6 , —C(O)—NHR 6 , or —S(O) 2 R 6 , wherein R 6 is H, alkyl, haloalkyl, aryl, or heteroaryl optionally substituted with one to four R 4 groups; and
R 4 is halo, —OR 7 , —N(R 7 ) 2 , —S(R 7 ) 2 , —S(O) 2 R 7 , —S(O) 2 N(R 7 ) 2 , —S(O) 2 OR 7 , —N(R 7 )S(O) 2 R 7 , —OS(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)N(R 7 ) 2 , —OC(O)R 7 , —OC(O)OR 7 , —OC(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)N(R 7 ) 2 , —CN, —NO 2 , alkyl, haloalkyl, alkyl-OR 7 , or alkyl-N(R 7 ) 2 , where each R 7 is independently H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl.
2. A method for inhibiting a small ubiquitin-like modifier enzyme in a cell, comprising administering to the cell a compound having the structure:
3. The method of claim 1 or claim 2 , wherein the small ubiquitin-like modifier enzyme is small ubiquitin-like modifier enzyme E1 or small ubiquitin-like modifier enzyme E2.