Nitrogen-Fused Ring Compounds Targeting DNA Polymerase Theta
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Solution Overview
Problem
Existing polymerase theta inhibitors have a relatively uniform structure, limiting their effectiveness in targeting DNA polymerase theta for cancer treatment, particularly in tumors with high expression levels.
Innovation Solution
Development of fused-ring nitrogen-containing compounds that enhance ATPase activity and protein inhibition, specifically designed to target DNA polymerase theta, which is highly expressed in various tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If existing polymerase theta inhibitors with uniform structure are used, then the structure is simple and easy to manufacture, but the inhibition efficacy is limited and cannot effectively target DNA polymerase theta in tumors with high expression levels
Solution Approach 1:
The patent applies composite material principles by designing inhibitors with complex fused-ring nitrogen-containing structures that combine multiple aromatic rings and heteroatoms. This composite structural approach enhances the inhibition efficacy against DNA polymerase theta while maintaining synthetic feasibility through modular construction of the molecular framework.
Solution Approach 2:
The patent employs parameter changes by systematically varying structural parameters such as ring size, heteroatom composition, substitution patterns, and molecular weight of the inhibitors. These parameter modifications optimize the binding affinity and inhibition efficacy against DNA polymerase theta, transforming the limited efficacy of uniform structures into high-performance inhibitors.
2Productivity
If existing polymerase theta inhibitors are used, then the development process is straightforward, but the therapeutic effectiveness in cancer treatment is insufficient
Solution Approach 1:
The patent systematically changes key molecular parameters including ring structure configuration, heteroatom types and positions, substituent groups, and molecular weight to develop inhibitors with enhanced therapeutic effectiveness. This parameter optimization approach maintains efficient development while achieving superior cancer treatment outcomes.
Solution Approach 2:
The patent develops composite molecular structures with fused-ring nitrogen-containing frameworks that provide enhanced therapeutic effectiveness. The composite nature of these inhibitors, combining multiple functional moieties, enables both efficient development and superior therapeutic outcomes in cancer treatment.
3Ease of manufacture
If simple structure inhibitors are used, then the synthesis is easier and cost is lower, but the ATPase activity and protein inhibition are insufficient
Solution Approach 1:
The patent optimizes molecular parameters such as ring system complexity, heteroatom content, and substituent patterns to enhance ATPase activity and protein inhibition capability. These parameter changes enable the synthesis of high-performance inhibitors with improved biochemical activity while maintaining reasonable synthetic complexity.
Solution Approach 2:
The patent employs composite molecular structures with fused-ring nitrogen-containing frameworks that inherently provide enhanced ATPase activity and protein inhibition. The composite structure design allows for improved biochemical potency through the synergistic arrangement of multiple functional elements.
Data Source
AI summary
Disclosed are a nitrogen-containing fused ring compound as shown informula (I), an intermediate thereof, a preparation method therefor and the use thereof. The compound has a DNA polymerase θ inhibitory activity, and can be used for treatingdiseases mediated by the DNA polymerase θ, such as tumors.