DNA-PK Inhibitor Crystal Forms Overcoming Tumor Resistance
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Solution Overview
Problem
Current chemoradiotherapy treatments for tumors face challenges due to high DNA-PK expression in tumor tissues, leading to enhanced DNA repair and reduced treatment efficacy, with tumor cells becoming resistant to chemotherapy and radiotherapy.
Innovation Solution
Development of a DNA-PK small molecule inhibitor in the form of a heterocyclic substituted purinone derivative, specifically in crystal forms A, B, and their salts, which exhibit excellent DNA-PK kinase inhibitory activity, improving pharmacokinetics and oral bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemoradiotherapy is used to treat tumors, then tumor cells are damaged, but high DNA-PK expression enhances DNA repair and reduces treatment efficacy
Solution Approach 1:
The patent converts the harmful effect of enhanced DNA repair into a benefit by using DNA-PK inhibitors to block this repair mechanism. The high DNA-PK expression that normally protects tumor cells is targeted by the inhibitor, turning the tumor's survival mechanism into its vulnerability, thereby restoring treatment efficacy
Solution Approach 2:
The DNA-PK inhibitor serves as an intermediary substance that mediates between the chemoradiotherapy treatment and the DNA repair process. It selectively blocks DNA-PKcs activity, preventing the repair of radiation-induced DNA breaks while allowing the therapeutic damage to accumulate in tumor cells
2Reliability
If DNA-PK inhibitors are developed to overcome resistance, then sensitivity to chemoradiotherapy is enhanced, but the complexity of the treatment regimen increases
Solution Approach 1:
The patent merges the DNA-PK inhibitor with existing chemoradiotherapy regimens into a unified treatment approach. By combining the inhibitor with conventional treatments, it creates a synergistic effect that enhances sensitivity while managing complexity through integrated treatment protocols
Solution Approach 2:
The DNA-PK inhibitor demonstrates multi-functionality by working across different tumor types (solid tumors and hematological tumors) and different treatment modalities (chemotherapy and radiotherapy). This universal applicability simplifies the overall treatment strategy by using a single agent to overcome resistance in multiple contexts
3Reliability
If DNA-PK inhibitors are used as single agents, then therapeutic effects are achieved in tumors with DNA repair pathway defects, but the scope of applicable tumors is limited
Solution Approach 1:
The patent applies the inhibitor dynamically in two distinct treatment scenarios: as a single agent for tumors with DNA repair pathway defects and in combination with chemoradiotherapy for other tumors. This dynamic adaptability allows the same inhibitor to achieve therapeutic effects across different tumor types and treatment contexts
Data Source
AI summary
Disclosed are a salt form and a crystal form of a heterocyclic substituted purinone derivative and a preparation method therefor. Specifically disclosed are a salt form and a crystal form of a compound of formula (I) and a preparation method therefor.