Imidazolinone DNA-PK Inhibition to Sensitize Tumors to Radiotherapy
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Solution Overview
Problem
Current radiotherapy treatments for malignant tumors vary in patient response, with some patients not benefiting and developing worsening progression due to enhanced DNA damage repair mechanisms, particularly DNA-PK activity, for which there are no effective inhibitors on the market.
Innovation Solution
The use of an imidazolinone derivative as a DNA-PK inhibitor in combination with radiotherapy to enhance tumor sensitivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional long-term radiotherapy is used to treat malignant tumors, then some patients can achieve complete pathological remission, but many patients do not benefit and develop worsening progression due to enhanced DNA damage repair mechanisms
Solution Approach 1:
The patent introduces DNA-PK inhibitors as intermediary substances that mediate between radiotherapy and tumor cells. These inhibitors block the DNA-PK pathway, preventing the tumor cells from repairing radiation-induced DNA damage, thereby enhancing radiotherapy effectiveness without directly causing damage themselves
Solution Approach 2:
The patent modifies the biochemical parameters of the DNA repair pathway by introducing inhibitors that change the activity state of DNA-PK. This parameter change (from active repair to inhibited state) transforms the tumor cells' response to radiotherapy, making them more sensitive to radiation damage
2Reliability
If DNA-PK activity is increased to repair DNA double-strand breaks, then tumor cell survival is improved, but radiotherapy killing effect is reduced
Solution Approach 1:
The patent converts the harmful effect of radiotherapy (DNA damage) into a beneficial outcome by using DNA-PK inhibitors to block the repair pathway. The radiation-induced DNA damage, which would normally be repaired and allow tumor survival, is instead exploited as a lethal effect when repair is inhibited
Solution Approach 2:
The patent applies preliminary anti-action by pre-treating tumor cells with DNA-PK inhibitors before radiotherapy. This preliminary inhibition of the DNA-PK pathway prevents the cells from mounting an effective repair response during subsequent radiation treatment, thereby enhancing killing effect
3Ease of manufacture
If no effective DNA-PK inhibitor drugs are available, then developing new inhibitors is challenging, but the clinical significance of such development is high
Solution Approach 1:
The patent modifies the chemical structure parameters of existing imidazolinone compounds to create novel DNA-PK inhibitors with optimized properties. By changing molecular parameters (substituents, functional groups), the patent achieves effective inhibition activity while addressing development challenges
Solution Approach 2:
The patent segments the drug development process by focusing on specific structural modifications of the imidazolinone core. This segmentation allows systematic exploration of structure-activity relationships, making the development process more manageable and efficient
Data Source
AI summary
The present invention provides the use of a compound represented by general formula (I) in combination with radiotherapy in a medicament for treating cancers