Deoxy-Cytidine and Uridine Derivatives Against CDA-Driven Drug Resistance
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Solution Overview
Problem
Current cancer therapies, particularly for glioblastoma multiforme, face challenges such as drug resistance, off-target cytotoxicity affecting healthy cells, and inefficacy against CDA-inactivated agents like gemcitabine and cytarabine, necessitating the development of more specific and effective anticancer agents.
Innovation Solution
Development of a class of compounds, including deoxy-cytidine and uridine derivatives with specific functional groups, which can inhibit tumor cell proliferation and are resistant to inactivation by cytidine deaminase, offering both monotherapy and synergistic effects when combined with other anticancer agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If broadly cytotoxic anticancer agents are used to kill a wide range of cancer cell types, then the ability to treat multiple cancer types is improved, but cytotoxicity against non-cancerous cells increases
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I) that exhibit differential toxicity based on cellular context. The compounds contain specific functional groups and structural features that allow them to selectively target cancer cells while sparing normal cells, achieving localized therapeutic effect at the molecular level.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as R1, R2, R3 substituents, and structural moieties in Formula I compounds. These parameter variations enable optimization of the therapeutic window, allowing the compounds to maintain broad anticancer activity while reducing off-target cytotoxicity through precise molecular tuning.
2Reliability
If known anticancer agents are used to treat cancer, then cancer cell proliferation is inhibited, but drug resistance develops
Solution Approach 1:
The patent uses intermediaries by designing compounds that act through novel mechanisms of action distinct from existing anticancer agents. The Formula I compounds interfere with cancer cell proliferation through unique biochemical pathways, bypassing resistance mechanisms that have developed against conventional therapies.
Solution Approach 2:
The patent applies composite materials principles by creating compounds with complex molecular architectures combining multiple functional groups and structural elements in Formula I. This composite structure enables multifaceted interaction with cancer cells, providing both direct cytotoxicity and inhibition of resistance development.
3Reliability
If CDA-inactivated agents like gemcitabine and cytarabine are used, then anticancer activity is achieved in CDA-negative tumors, but efficacy is lost in CDA-positive tumors
Solution Approach 1:
The patent applies universality by designing Formula I compounds that function effectively regardless of CDA expression status. These compounds possess structural features that make them resistant to CDA-mediated inactivation while maintaining their anticancer activity, enabling them to serve as universal agents across tumors with varying CDA expression levels.
Solution Approach 2:
The patent converts the potential harm of CDA expression into a benefit by designing compounds that are specifically stable against CDA degradation. The structural features of Formula I compounds include elements that protect against deamination, effectively using the presence of CDA as a marker for selecting stable, resistant compounds that maintain activity in all tumor types.
Data Source
AI summary
The present invention relates to a compound of Formula (I):or a stereoisomer, solvate, tautomer or pharmaceutically acceptable salt thereof, wherein X, W1, W2, Y, Z, R1, R2 and R3 are as defined in the disclosure herein, for use in therapy, particularly for use in the treatment of cancer. The present invention also relates to methods of treating cancer comprising the administration of a compound of Formula (I) to asubject in need thereof, and to pharmaceutical compositions and kits comprising such compounds.