P-glycoprotein Inhibitors Reversing Multidrug Resistance
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Solution Overview
Problem
Current chemotherapy treatments for cancer are hindered by multidrug resistance due to the over-expression of P-glycoprotein, which effluxes chemotherapeutic agents from cancer cells, leading to treatment failure and recurrence, especially in cancer stem cells and across the blood-brain barrier.
Innovation Solution
Development of P-glycoprotein inhibitors that specifically target the nucleotide binding domains, minimizing transport by P-glycoprotein while blocking chemotherapeutic drug export, thereby re-sensitizing resistant cancer cells to chemotherapy and enhancing drug penetration through barriers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If P-glycoprotein is over-expressed to efflux chemotherapeutic agents, then cancer cells develop multidrug resistance, but chemotherapeutic agents cannot accumulate in cancer cells leading to treatment failure
Solution Approach 1:
The patent introduces P-glycoprotein inhibitors as intermediary substances that block the efflux pump mechanism. These inhibitors bind to P-glycoprotein and prevent it from transporting chemotherapeutic agents out of cancer cells, thereby allowing the chemotherapeutic agents to accumulate and exert their cytotoxic effects.
Solution Approach 2:
The patent modifies the chemical structure of chemotherapeutic agents by conjugating them with amino acid residues (such as L-amino acids, D-amino acids, or their derivatives). This structural modification changes the parameters of the drug molecule, specifically reducing its recognition and transport by P-glycoprotein while maintaining its anticancer activity.
2Productivity
If conventional chemotherapeutic agents are used, then they can kill proliferating cancer cells, but they are effluxed by P-glycoprotein reducing their intracellular concentration and efficacy
Solution Approach 1:
The patent changes the chemical parameters of chemotherapeutic agents through conjugation with amino acid residues. This modification alters the molecular properties such as hydrophobicity, charge, and steric configuration, which collectively reduce the affinity of the drug for P-glycoprotein binding sites and transport mechanisms.
Solution Approach 2:
P-glycoprotein inhibitors serve as intermediary molecules that occupy the binding sites on P-glycoprotein, preventing the efflux of chemotherapeutic agents. This intermediary action allows the chemotherapeutic agents to remain in the cell at effective concentrations for longer periods.
3Reliability
If P-glycoprotein inhibitors are designed to block drug transport, then they can reverse multidrug resistance, but the inhibitors themselves may be transported by P-glycoprotein reducing their intracellular accumulation
Solution Approach 1:
The patent modifies the chemical structure of P-glycoprotein inhibitors by conjugating them with amino acid residues. This structural modification changes the physical and chemical parameters of the inhibitor, reducing its recognition by P-glycoprotein transport mechanisms while maintaining its inhibitory activity against the efflux pump.
Data Source
AI summary
The present disclosure provides a method of treating a subject that is resistant to one or more drugs by identifying a subject having one or more drug resistant cells; administering to the subject a pharmaceutically effective amount of an inhibitor compound, and contacting one or more drug resistant cells with the inhibitor compound to reduce the export of the inhibitor compound from the one or more drug resistant tumor cells and to block the transport of drug(s) from the one or more drug resistant cells.