Indole Prodrug Conjugates for Solubility-Limited Cancer Therapy
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Solution Overview
Problem
Existing indole derivatives targeting KIF20A have poor water solubility, which hinders their effective concentration in systemic circulation and absorption, posing a challenge for pharmacological response in cancer treatment.
Innovation Solution
Development of highly soluble prodrugs derived from indole derivatives, where the nitrogen atom is linked to phosphonic acid containing promoieties or cleavable groups, enhancing solubility and facilitating intracellular and extracellular drug release through protein conjugates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If indole derivatives are used as MKlp2 inhibitors, then therapeutic efficacy is improved, but water solubility deteriorates
Solution Approach 1:
The patent introduces a prodrug approach where indole derivatives are converted into water-soluble prodrugs through linkage with phosphonic acid promoieties or cleavable groups. These prodrugs act as intermediaries that improve water solubility and facilitate drug release, thereby resolving the contradiction between therapeutic efficacy and water solubility
Solution Approach 2:
The patent modifies the chemical parameters of indole derivatives by introducing phosphonic acid groups and cleavable linkers, changing the molecular properties to enhance water solubility while maintaining the ability to release the active drug compound, thus resolving the solubility-efficacy contradiction
2Reliability
If indole derivatives are administered systemically, then pharmacological response is achieved, but poor solubility hinders effective concentration in circulation
Solution Approach 1:
The prodrugs serve as intermediaries that facilitate the absorption and circulation of the drug compound. The water-soluble prodrug form enables efficient systemic administration and circulation, while the cleavable groups ensure release of the active compound at the target site, resolving the contradiction between pharmacological response and absorption efficiency
3Duration of action of stationary object
If protein conjugates are used to enhance solubility and circulation, then circulating half-life is increased, but molecular complexity increases
Solution Approach 1:
The patent segments the drug molecule into distinct functional modules: the indole derivative core, the phosphonic acid prodrug moiety, and the cleavable linker group. This segmentation allows for modular design that can be systematically optimized to extend circulating half-life through protein conjugation while managing molecular complexity through structured organization
Data Source
AI summary
The present invention relates to N-substituted derivatives of indoles of formula (I):and their use in the treatment of cancer. The invention further provides protein-drug conjugates, more particularly antibody-drug conjugates, from compounds of formula (I).