This technology employs small molecule compounds that target human apurinic/apyrimidinic endonuclease-1 (APE1) by binding directly to its active site. These molecules are structured with a dual-domain design: one domain comprises a 6,7-methylenedioxy-4-aminoquinoline unit, while the other is optimized for π-cation interactions with arginine 177 of APE1. The two domains are joined by a linker, which may be flexible or rigid, typically incorporating a hydrazone group or alternatives like amides, carbamates, ureas, and cyclic linkers such as pyrazole or imidazole. Synthesizing these compounds involves separately preparing key subunits before a strategic coupling, and extensive characterization confirms nanomolar-level inhibition of APE1 endonuclease activity while minimally interfering with DNA intercalation.
Description
This approach is differentiated by its precise targeting of APE1’s endonuclease function while preserving its redox activity. Comprehensive molecular modeling and in vitro assays validate its specificity and potency. Additionally, the compounds enhance the effectiveness of DNA-damaging agents, offering significant therapeutic potential against resistant cancer cells. This selectivity and innovative design mark a substantial advancement over previous methods that lacked effective binding or exhibited limited cellular activity.
Applications
- Cancer combination therapy
- Chemotherapy adjuvant agent
- Drug resistance reversal
- DNA repair research tool
Advantages
- Potent nanomolar-level inhibition of APE1 endonuclease activity for effective disruption of DNA repair.
- Minimal DNA intercalation, ensuring targeted protein inhibition without compromising DNA integrity.
- Enhancement of the cytotoxic effects of DNA-damaging agents in cancer cells, potentially overcoming drug resistance.
- Selective toxicity towards certain cancer cell types, including leukemia and melanoma, supporting therapeutic precision.
- Preservation of APE1’s redox function while inhibiting its repair activity, offering a unique mechanism of action.
- Versatile molecular design enabling both the development of research tools for APE1 function studies and potential therapeutic agents.
IP Status
https://patents.google.com/patent/US9624235B2
