Multi-Target Compounds Inhibiting PARP RNR and HR Repair
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Solution Overview
Problem
Current PARP inhibitors are limited in effectiveness for epithelial ovarian cancer, particularly for BRCA-mutated cases and those with HR deficiency, and resistance to these inhibitors is a growing concern due to reversion of mutated BRCA genes, necessitating new compounds and methods to inhibit PARP, RNR, and HR repair.
Innovation Solution
Development of compounds represented by Formulae (I) to (V) that inhibit ribonucleotide reductase (RNR), poly ADP-ribose polymerase (PARP), and homologous recombination (HR) repair, which can be used in compositions with existing PARP inhibitors like olaparib to enhance cancer treatment efficacy, particularly for BRCA-wild type cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If PARP inhibitors are used to treat epithelial ovarian cancer, then treatment options are expanded for BRCA-mutated and HR-deficient cancers, but effectiveness is limited to only 15-50% of cases and resistance develops due to BRCA gene reversion
Solution Approach 1:
The patent segments the DNA repair pathway into multiple targets by developing compounds that simultaneously inhibit PARP, RNR, and HR repair mechanisms. This multi-target approach divides the monolithic PARP inhibition strategy into coordinated attacks on different repair pathways, preventing cancer cells from developing resistance through single mechanisms like BRCA reversion.
Solution Approach 2:
The patent employs composite therapeutic strategies by combining compounds with multiple inhibitory activities (PARP, RNR, and HR inhibition) into single therapeutic agents. This composite approach integrates multiple mechanisms of action within one compound, thereby expanding treatment versatility while maintaining durability through redundant targeting of DNA repair pathways.
2Adaptability or versatility
If compounds are developed to inhibit multiple pathways (PARP, RNR, HR repair), then treatment versatility for resistant cancers is improved, but compound complexity increases
Solution Approach 1:
The patent applies universality by designing compounds that perform multiple functions simultaneously - inhibiting PARP, RNR, and HR repair pathways. This multi-functional design allows a single compound to address multiple resistance mechanisms without requiring separate agents, thereby achieving broad adaptability while managing complexity through functional integration rather than structural complexity.
Solution Approach 2:
The patent utilizes parameter changes by modifying compound properties to achieve multi-pathway inhibition. By adjusting molecular parameters such as functional group composition, steric properties, and electronic characteristics, the compounds are optimized to interact with multiple targets (PARP, RNR, HR proteins) while maintaining manageable structural complexity through systematic parameter optimization.
Data Source
AI summary
The present invention relates to compounds represented by Formulae (I) to (V), or a racemate, enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, hydrate, or derivative thereof, and compositions thereof. In various aspects, the present invention also relates to methods of reducing or inhibiting ribonucleotide reductase (RNR), poly ADP-ribose polymerase (PARP), and/or homologous recombination (HR) repair using said compounds. In some aspects, the present invention relates to methods of inducing at least one double strand break (DSB) using said compounds. In another aspect, the present invention relates to methods of treating or preventing cancer (e.g., ovarian cancer, BRCA-wild type cancer, etc.) using said compounds.