ERCC1-XPF Inhibitors for Selective DNA Repair Blockade
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Solution Overview
Problem
Current ERCC1-XPF inhibitors lack specificity for the complex, leading to non-specific DNA repair inhibition and undesirable side effects on normal cells, limiting their effectiveness in cancer treatment.
Innovation Solution
Development of novel ERCC1-XPF complex inhibitors through structure-based virtual screening, targeting the interaction between ERCC1 and XPF, with specific compounds designed to destabilize the complex and enhance cisplatin-induced cytotoxicity in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current ERCC1-XPF inhibitors are used to target the complex, then DNA repair inhibition is achieved, but specificity is lost leading to side effects on normal cells
Solution Approach 1:
The patent applies local quality by designing inhibitors that specifically target the ERCC1-XPF complex interface with precise molecular interactions. The compounds are engineered to bind selectively to specific residues at the complex interface, ensuring localized and specific inhibition of the DNA repair pathway without affecting other cellular processes or normal cells indiscriminately.
Solution Approach 2:
The patent employs small molecule compounds as intermediaries that mediate the inhibition of ERCC1-XPF complex function. These compounds act as molecular mediators that disrupt the protein-protein interaction between ERCC1 and XPF, thereby blocking DNA repair activity in a targeted manner while sparing normal cellular functions that do not involve this specific complex interface.
2Productivity
If ERCC1-XPF complex is inhibited to enhance chemotherapy efficacy, then cancer cell sensitivity to DNA-damaging agents increases, but off-target effects occur
Solution Approach 1:
The patent applies segmentation by focusing inhibition on a specific functional segment of the DNA repair pathway - the ERCC1-XPF complex interface. Rather than broadly inhibiting all DNA repair mechanisms, the compounds selectively disrupt this specific protein-protein interaction segment, thereby enhancing chemotherapy efficacy through targeted pathway blockade while minimizing disruption to other essential cellular processes.
Solution Approach 2:
The patent utilizes parameter changes by optimizing the molecular properties of the inhibitor compounds to achieve selective binding to the ERCC1-XPF complex. By carefully adjusting parameters such as molecular weight, hydrophobicity, and specific functional group positioning, the compounds achieve high affinity and specificity for the target complex while maintaining appropriate pharmacokinetic properties and minimizing off-target interactions.
Data Source
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AI summary
The present invention discloses ERCC1-XPF complex inhibitor compounds and the use thereof in the treatment of cancer, in combination therapy or as standalone treatment. The invention further extends to pharmaceutical compositions that comprise an effective amount of these compounds, as well as kits comprising of the compounds and at least one anticancer agent, therefore providing a tailored approach for the treatment of specific cancers, such as non-small cell lung cancer.