Uracil Compounds Inhibit dUTPase to Overcome Chemotherapy Resistance
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Solution Overview
Problem
Current chemotherapies targeting thymidylate metabolism, such as 5-fluorouracil, face significant challenges due to drug resistance, particularly mediated by elevated levels of deoxyuridine triphosphatase (dUTPase, which limits the effectiveness of these treatments in cancer patients.
Innovation Solution
Development of compounds and compositions that inhibit dUTPase, either alone or in combination with dUTPase-directed chemotherapies, to enhance the sensitivity of cancer cells to thymidylate synthase inhibitors, thereby overcoming resistance and improving treatment outcomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dUTPase levels are elevated to protect against uracil misincorporation, then drug resistance to thymidylate synthase inhibitors increases, but this protective mechanism reduces the efficacy of chemotherapeutic agents
Solution Approach 1:
The patent introduces dUTPase inhibitors as intermediary compounds that block the protective dUTPase enzyme, thereby preventing it from counteracting the effects of thymidylate synthase inhibitors. This mediator approach eliminates the harmful protective mechanism while preserving the therapeutic action of chemotherapy drugs
Solution Approach 2:
The patent changes the biochemical parameters by introducing compounds that specifically inhibit dUTPase activity, altering the enzymatic balance in favor of enhancing chemotherapeutic efficacy. This parameter change prevents dUTP pool expansion and uracil misincorporation protection that would otherwise resist drug action
2Productivity
If thymidylate synthase inhibitors are used to treat cancer, then DNA replication is blocked in dividing cells, but drug resistance develops due to dUTPase overexpression
Solution Approach 1:
The patent combines dUTPase inhibition with thymidylate synthase inhibition in a unified therapeutic strategy. By merging these two mechanisms, the patent creates a synergistic effect where dUTPase inhibitors enhance the DNA replication blockade caused by TS inhibitors, preventing resistance development
Solution Approach 2:
The patent employs preliminary inhibition of dUTPase to prevent the development of resistance mechanisms before they can activate. By blocking dUTPase activity in advance, the patent ensures that cancer cells remain sensitive to subsequent or concurrent thymidylate synthase inhibitor treatment
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The proposed compounds effectively inhibit dUTPase, potentially reversing resistance to dUTPase-directed chemotherapies and enhancing their efficacy, leading to improved therapeutic benefits for cancer treatment.
Implementation Method 1
compounds and compositions that inhibit dUTPase when used alone or in combination with at least one dUTPase-directed chemotherapy
Data Source
AI summary
Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.