Inhibition of small ubiquitin-like modifier enzymes with substituted pyrrolo[2,3-b]quinoxalines

摘要

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.

主权项

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 R1 and R2 are independently selected from the group consisting of H, —S(O)2—R8, —CN and —C(O)—X—R9; wherein R8 is an alkyl, or aryl; wherein R9 is an alkyl, aryl, or heteroaryl; wherein X is selected from the group consisting of CH2, O, NH, and S; wherein R3 is selected from the group consisting of an alkyl, an alkenyl, and an alkylaryl; wherein each of R4, R5, R6 and R7 are independently selected from the group consisting of H, a halogen, and an alkyl; wherein X1 is selected from the group consisting of CH2, NH, O, and S; and wherein X2, X3 and X4 are N; or and pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in all ratios, wherein: A and B are N; R1 is H, alkyl, haloalkyl, alkyl-OR1, aryl, heterocyclyl, benzyl, or alkyl-aryl where R1 is optionally substituted with one to four R4 groups; R2 is H or L-R5, wherein L is —C(O)— or —S(O)2—, and R5 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, benzyl, or alkyl-aryl optionally substituted with one to four R4 groups; R3 is CN, —C(O)—OR6, —C(O)—NHR6, or —S(O)2R6, wherein R6 is H, alkyl, haloalkyl, aryl, or heteroaryl optionally substituted with one to four R4 groups; and R4 is halo, —OR7, —N(R7)2, —S(R7)2, —S(O)2R7, —S(O)2N(R7)2, —S(O)2OR7, —N(R7)S(O)2R7, —OS(O)2R7, —C(O)R7, —C(O)OR7, —C(O)N(R7)2, —OC(O)R7, —OC(O)OR7, —OC(O)N(R7)2, —N(R7)C(O)R7, —N(R7)C(O)OR7, —N(R7)C(O)N(R7)2, —CN, —NO2, alkyl, haloalkyl, alkyl-OR7, or alkyl-N(R7)2, where each R7 is independently H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl.