BLM-RAD54 Interaction Inhibitors for Chemoresistance
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Solution Overview
Problem
Cancer cells develop chemoresistance due to heightened DNA repair capacity, particularly through the interaction of Bloom syndrome protein (BLM) and RAD54, which enhances homologous recombination repair, leading to resistance against chemotherapeutic agents like cisplatin and camptothecin.
Innovation Solution
Administering inhibitors of the BLM-RAD54 interaction, such as Azaguanine-8, Allantoin, Acetazolamide, and other small molecules, in conjunction with chemotherapy to disrupt this interaction and reduce chemoresistance in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cancer cells utilize DNA repair pathways (BLM-RAD54 interaction) to repair damaged DNA, then cell survival is improved, but chemoresistance increases
Solution Approach 1:
The patent extracts and inhibits the specific BLM-RAD54 interaction component from the DNA repair pathway using small molecule inhibitors. By targeting this specific protein-protein interaction interface, the patent selectively disrupts the harmful chemoresistance mechanism while preserving other essential cellular functions that depend on DNA repair pathways.
Solution Approach 2:
The patent introduces small molecule inhibitors as intermediary substances that mediate between the BLM and RAD54 proteins. These inhibitors act as molecular mediators that block the direct interaction between BLM and RAD54, preventing the formation of the functional complex that confers chemoresistance without completely abolishing DNA repair capacity.
2Productivity
If chemotherapeutic agents are used to damage DNA in cancer cells, then cancer cell elimination is improved, but DNA repair mechanisms are activated leading to resistance
Solution Approach 1:
The patent applies preliminary action by administering BLM-RAD54 interaction inhibitors either concurrently with or immediately following chemotherapeutic agents. This timing strategy prevents the activation and effectiveness of DNA repair mechanisms before they can counteract the chemotherapeutic damage, thereby maintaining therapy effectiveness over time and preventing resistance development.
Solution Approach 2:
The patent implements preliminary anti-action by pre-emptively blocking the BLM-RAD54 interaction pathway that would otherwise repair chemotherapeutic damage. By inhibiting this repair pathway in advance or concurrently with chemotherapy administration, the patent prevents the counter-action of DNA repair that would otherwise reduce therapy effectiveness.
3Productivity
If BLM and RAD54 proteins interact to perform homologous recombination repair, then DNA repair efficiency is improved, but chemotherapeutic agent efficacy is reduced
Solution Approach 1:
The patent uses small molecule inhibitors as intermediary substances that specifically block the BLM-RAD54 protein-protein interaction interface. These inhibitors bind to one or both proteins at their interaction interface, preventing the formation of the functional complex required for efficient homologous recombination repair, thereby reducing DNA repair efficiency specifically for chemotherapeutic resistance without affecting other cellular processes.
Data Source
AI summary
The present disclosure shows that a stretch of 32 amino acids in BLM interacts with RAD54 and this interaction contributes to resistance against chemotherapeutic drugs such as cisplatin, camptothecin, oxaliplatin, etc. in cancer cells. The present disclosure provides an inhibitor of BML-RAD54 interaction as an adjunct therapy for treating cancer in a patient, wherein the patient is receiving primary chemotherapy. In some embodiments, the inhibitor of BML-RAD54 interaction is selected from Azaguanine-8, Allantoin, Acetazolamide, Metformin, Atracurum, Prednisone, Dipyridamole, Metronidazole, Khellin, Apomorphine, Naloxone, Bromocryptine, Glipizide, Verapamil, Erythromycin, Chloroxine, Loxapine, a pharmaceutically acceptable salt thereof, or a combination thereof.