| 摘要 |
Targeting uncontrolled cell proliferation and resistance to DNA damaging chemotherapeutics with at least one reagent has significant potential in cancer treatment. Replication Protein A, the eukaryotic single-strand (ss) DNA binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. Reported herein are small molecules that inhibits the in vitro, in vivo, and cellular ssDNA binding activity of RPA, thereby disrupting the eukaryotic cell cycle, inducing cytotoxicity and increasing the efficacy of chemotherapeutic agents damage DNA, and/or disrupt its replication and/or function. These results provide new insights into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. This represents a molecularly targeted eukaryotic DNA binding inhibitor and demonstrates the utility of targeting a protein-DNA interaction as a means of studying the cell cycle and providing a therapeutic strategy for cancer treatment. |
| 主权项 |
1. A method of reducing the activity of a protein, comprising the steps of:
providing a compound A or a pharmaceutically acceptable salt thereof, wherein said compound A binds to Replication Protein A or is metabolized into a chemical that binds to Replication Protein A, said compound A having the following formula: wherein, R1 is selected from the group consisting of: substituted quinolins, thiophenes and phenyls; including 5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl); 5-(quinoxalin-6-yl); and 6-chloro-[1,3]dioxolo[4,5-g]quinolin-7-yl R2 is selected from the group consisting of: hydrogen, halogens, methyl groups, nitro groups; wherein compound A or a metabolite of compound A binds to Replication Protein A; and R3 is selected from the group consisting of: ketobutyric acids, and wherein n=1, 2, 3, 4, or 5; and contacting said compound A with at least one isoform of Replication Protein A. |
