Purine DNA-PK Inhibitors With Higher Selectivity for Cancer Sensitization
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Solution Overview
Problem
Current DNA-PK inhibitors suffer from high toxicity and poor selectivity, limiting their clinical application in cancer treatment.
Innovation Solution
Development of purine derivatives with high inhibitory activity and selectivity for DNA-PK, designed as chemosensitizers and radiosensitizers to enhance cancer treatment efficacy while minimizing toxic side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DNA-PK inhibitors are used to treat cancer, then the efficacy of cancer treatment is improved, but toxicity and selectivity issues arise
Solution Approach 1:
The patent modifies molecular parameters of DNA-PK inhibitors by introducing specific substituents (R1-R6) at defined positions on the core structure, optimizing the balance between inhibitory activity and selectivity. This includes varying substituent types (halogens, alkyl groups, aryl groups) and their positions to achieve desired pharmacological properties while reducing toxicity.
Solution Approach 2:
The patent creates composite molecular structures by combining a core DNA-PK inhibitor scaffold with various functional groups and substituents. These composite structures integrate multiple pharmacophores that work synergistically to enhance cancer cell killing while sparing normal cells, thereby improving selectivity and reducing toxicity.
2Reliability
If DNA-PK inhibitors interfere with DNA repair function, then tumor cell killing is enhanced, but normal cell damage may occur
Solution Approach 1:
The patent introduces substituents at specific local positions (R1-R6) on the inhibitor molecule that target DNA-PK isoforms preferentially expressed in tumor cells. This local modification strategy enables selective inhibition of DNA-PK in cancer cells while preserving normal cell DNA repair function, thereby enhancing tumor cell killing without causing significant normal cell damage.
Solution Approach 2:
The patent designs inhibitors that act as intermediaries between chemotherapy/radiation therapy and DNA repair pathways. These compounds selectively modulate DNA-PK activity in tumor cells to enhance the effectiveness of conventional therapies while sparing normal cells through their selective binding properties and metabolic differences.
3Reliability
If existing DNA-PK inhibitors are used, then some inhibitory activity is achieved, but selectivity and toxicity limitations prevent clinical application
Solution Approach 1:
The patent creates a series of dynamic analogs with varying substituent patterns that can adapt to different DNA-PK binding conformations. This dynamic structural approach allows the inhibitors to maintain high binding affinity and selectivity while minimizing off-target effects and toxicity, overcoming the limitations of static inhibitor structures.
Data Source
AI summary
The present invention relates to a purine derivative and use thereof in medicine, and in particular to a pyrimidine derivative shown as general formula (I) or a stereoisomer, solvate, metabolite, prodrug, deuteride, pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutical composition comprising the same, and use of the compound or composition of the present invention in the field of preparation of a DNA-PK inhibitor, wherein the substituents in general formula (I) are defined in the same way as in the specification