Compositions and methods for disruption of BRCA2-Rad51 interaction
View Patent ↗Contemplated compounds disrupt interaction between BRCA2 and RAD51, likely by binding to RAD51. Based on the crucial role of the BRCA2-RAD51 complex formation in DNA repair and the role of RAD51 in the control of entry into S-phase from G1, numerous compositions and methods are presented. Among other advantageous uses, contemplated compounds may be employed as protective agents for non-neoplastic cells in chemotherapy before exposure of the cells to a chemotherapeutic drug, and/or as DNA-damage sensitizer for neoplastic cells.
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to Formula 1
wherein R is a radical selected from the group consisting of an alkenyl, alkynyl, benzyl, and
wherein Y is an alkylene group having 1 to 4 carbon atoms;
Z is selected from —CH═N—, —N═CH—, O, S, or NR 14 , where R 14 is H, alkyl, aryl, alkaryl, or acyl;
Q is N or C—R 2
X is selected from CH 2 , O, S, or NR 14 , where R 14 is independently as defined above;
R′ and R 1 through R 11 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, halo, nitro, hydroxy, alkoxy, alkenyloxy, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, amino, acylamino, alkylamino, dialkylamino, cycloalkylamino, N-alkyl, N-cycloalkyl, amino, thio, alkylthio, and haloalkyl; and
wherein n is between 0 and 4, inclusive, and wherein * denotes R or S configuration.
2. The pharmaceutical composition of claim 1 wherein R 1 through R 11 are H, wherein X is NR 14 , and wherein R is
3. The pharmaceutical composition of claim 1 wherein the compound has a structure according to Formula 3
4. The pharmaceutical composition of claim 1 wherein the compound is present in the composition at a concentration effective to increase sensitivity of a neoplastic cell to at least one of radiation and a DNA-damaging agent when the cell is exposed to the compound.
5. The pharmaceutical composition of claim 1 wherein the compound is present in the composition at a concentration effective to reduce binding of BRCA2 to RAD51 when a BRCA2-RAD51 complex is exposed to the compound.
6. The pharmaceutical composition of claim 1 further comprising a DNA-damaging agent.
7. The pharmaceutical composition of claim 1 wherein the compound is present in the composition at a concentration effective to arrest a cell in G1 phase when the cell is contacted with the compound.
8. The pharmaceutical composition of claim 1 wherein the compound is coupled to an implanted device at a concentration effective to reduce cell proliferation of a plurality of cells proximal to the implanted device.