FL118 Analogues Reduce Toxicity While Maintaining Antitumor Efficacy
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Solution Overview
Problem
Current cancer treatments, particularly those based on camptothecin analogues like irinotecan and topotecan, face challenges with treatment resistance and high toxicity due to their reliance on topoisomerase I inhibition, which limits their efficacy and increases side effects.
Innovation Solution
Development of FL118 platform-derived compounds that exhibit low inhibitory effects on topoisomerase I function while targeting multiple key disease-associated genes and gene products, offering high anticancer efficacy with reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If camptothecin analogues (irinotecan, topotecan) are used to treat cancer, then topoisomerase I inhibition intensity increases, but antitumor efficacy does not significantly improve while side-effect toxicities increase
Solution Approach 1:
The patent changes the chemical parameters of camptothecin analogues by modifying positions 7 and 9 of the core structure, creating FL118 and its derivatives. These structural parameter changes result in compounds that maintain antitumor efficacy while reducing dependence on topoisomerase I inhibition, thereby lowering hematopoietic toxicities associated with strong Top1 inhibition
Solution Approach 2:
Instead of following the conventional approach of strengthening topoisomerase I inhibition to improve antitumor efficacy, the patent inverts the strategy by designing compounds (FL118 derivatives) that exhibit low Top1 inhibition but maintain high antitumor activity through alternative mechanisms, thus breaking the traditional efficacy-toxicity trade-off
2Reliability
If camptothecin analogues with strong topoisomerase I inhibition are developed, then inhibition intensity increases, but treatment resistance develops and efficacy is limited
Solution Approach 1:
The patent creates FL118 derivatives that possess multiple functions: they can target multiple disease-associated genes and pathways beyond topoisomerase I, including genes involved in treatment resistance. This multi-functionality allows the compounds to overcome resistance mechanisms while maintaining efficacy across different cancer types and resistance states
Solution Approach 2:
The patent employs dynamic combinatorial chemistry to generate diverse FL118 derivatives with varying structures at positions 7 and 9. This dynamic approach allows selection of compounds optimized for specific therapeutic needs, including overcoming treatment resistance through alternative mechanisms rather than relying solely on topoisomerase I inhibition
Data Source
AI summary
Described herein, are the chemical synthesis, matter of compositions, formulation, function, methods and uses of the FL118 platform Positions 7 and/or 9-derived analogues for treating cancer or other human diseases. Compounds derived from chemical modifications of the FL118 platform are employed alone or in combination with other anti-cancer agents to preclude, eliminate or reverse cancer phenotypes. This invention intends to realize unique personalized cancer treatment (personalized precision medicine) through application of a series of structural relevant individual FL118 platform-derived analogues, which target multiple cellular human disease-relevant proteins and their signaling pathways.