Selective CDK2 Inhibitor Compounds for CCNE1-Driven Cancers
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Solution Overview
Problem
Current therapies lack effective CDK2 inhibitors that selectively target cyclin-dependent kinase 2 (CDK2) for cancer treatment, particularly in cancers with CCNE1 amplification or overexpression, leading to poor treatment outcomes.
Innovation Solution
Development of novel compounds that act as selective CDK2 inhibitors, effectively inhibiting CDK2 activity while minimizing impact on other CDK-family kinases, with potential for improved therapeutic efficacy and reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for cancer treatment, then treatment is provided, but effective CDK2 inhibition is not achieved leading to poor treatment outcomes
Solution Approach 1:
The patent applies parameter changes by modifying chemical structures (Formula I compounds with specific R1-R7 substituents) to optimize binding affinity to CDK2 while reducing affinity to other CDKs. This involves changing molecular parameters such as substituent types, positions, and configurations to achieve selective inhibition of CDK2 over CDK1, CDK4, and CDK6, thereby improving treatment efficacy for cancers with CCNE1 amplification
Solution Approach 2:
The patent applies local quality by designing specific regions of the molecule with distinct functions: the core structure (Formula I) provides CDK2 binding, while specific substituent groups (R1-R7) provide selectivity. Different substituents at different positions create local variations that enhance CDK2 selectivity while maintaining inhibition potency, allowing the molecule to selectively target CDK2 in cancers with CCNE1 overexpression
2Reliability
If selective CDK2 inhibitors are developed, then CDK2 inhibition is improved, but off-target toxicities may occur
Solution Approach 1:
The patent uses parameter changes to optimize the balance between potency and selectivity by systematically varying chemical parameters in Formula I compounds. By adjusting substituent parameters (R1-R7) to achieve optimal binding to CDK2's ATP-binding pocket while avoiding off-target binding to CDK1, CDK4, and CDK6, the compounds maintain high inhibition potency for CDK2 while minimizing off-target toxicities
Solution Approach 2:
The patent employs structural intermediaries (specific substituent groups in Formula I) that mediate between the goal of strong CDK2 inhibition and the need to avoid off-target effects. These intermediary structures facilitate selective binding to CDK2 through specific interactions (hydrogen bonding, hydrophobic interactions) while preventing binding to other CDKs, thereby reducing off-target toxicities
Data Source
AI summary
The present disclosure provides a compound represented by structural Formula (I):or a pharmaceutically acceptable salt thereof useful for treating a cancer.