Triarylpyridine compounds for lysosomal membrane permeabilization
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Solution Overview
Problem
Current anticancer therapies face challenges due to cancer cells becoming chemoresistant, with lysosomes playing a role in drug resistance by sequestering anticancer agents, and existing G-quadruplex ligands have limitations in efficacy against cancer cells.
Innovation Solution
Development of new triarylpyridine compounds that induce cancer cell death through lysosomal membrane permeabilization, potentially synergized with lysosomotropic agents like chloroquine to enhance their effectiveness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing G-quadruplex ligands are used to inhibit cancer proliferation, then cancer cell growth is suppressed to some extent, but the compounds fail to achieve sufficient efficacy and cancer remains life-threatening
Solution Approach 1:
The patent modifies the chemical structure of G-quadruplex ligands by changing molecular parameters - specifically incorporating triarylpyridine core with varying aryl substituents (R1-R6 groups) to optimize binding affinity and cellular penetration, thereby enhancing anticancer efficacy
Solution Approach 2:
The invention creates composite therapeutic strategies by combining triarylpyridine compounds with lysosomotropic agents (such as chloroquine), where the combination synergistically enhances cancer cell death through multiple mechanisms including G4 stabilization and lysosomal membrane permeabilization
2Reliability
If lysosomes are targeted to overcome chemoresistance, then drug resistance is reduced, but new compounds must be designed to achieve lysosomal membrane permeabilization which increases development complexity
Solution Approach 1:
The triarylpyridine compounds are designed to perform multiple functions simultaneously: binding to G-quadruplex DNA structures, penetrating cancer cell membranes, and inducing lysosomal membrane permeabilization, thereby reducing the need for multiple separate agents
Solution Approach 2:
The patent introduces lysosomotropic properties to the compounds through specific structural features that enable selective accumulation and action in lysosomes, creating localized high concentration effects at the target site while maintaining overall compound stability
3Reliability
If combination therapy with lysosomotropic agents is used, then synergistic efficacy is achieved, but treatment protocol complexity increases
Solution Approach 1:
The patent merges the functions of G-quadruplex stabilization and lysosomal membrane permeabilization induction into a single compound class (triarylpyridines), which can then be combined with lysosomotropic agents to create synergistic effects that target multiple resistance mechanisms simultaneously
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 new triarylpyridine compounds demonstrate improved activity in inducing cancer cell death, particularly through lysosomal membrane permeabilization, and show a synergistic effect when combined with chloroquine, surpassing the efficacy of existing compounds like 20A.
Implementation Method 1
G-quadruplexes (G4s) are four-stranded non-canonical nucleic acids secondary structures which form in guanine-rich DNA and RNA sequences. Many G-quadruplex forming sequences are found to be associated with cancer. Some compounds, named G-quadruplex interactive ligands (or G-quadruplex ligands, or G4 ligands, abbreviated as G4L) have been shown to strongly interact with G-quadruplex DNA and to inhibit cancer proliferation
Implementation Method 2
Lysosomal dependent non-apoptotic cell death is of tremendous interest in cancer therapy as cancer cells often display defective apoptotic machinery rendering them resistant to therapy. The new triarylpyridine compounds demonstrate improved activity in inducing cancer cell death, particularly through lysosomal membrane permeabilization
Implementation Method 3
There is a need to provide new compounds with a lysosomotropic effect. The new triarylpyridine compounds show a synergistic effect when combined with chloroquine, surpassing the efficacy of existing compounds like 20A
Data Source
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AI summary
The invention relates to new bis-triazole 2,4,6-triarylpyridines compounds and their use in the field of oncology, in particular in the prevention and/or treatment of cancer disease. The inventors have observed that the new bis-triazole 2,4,6-triarylpyridines were able to induce cancer cells death either as a standalone or, synergistically, in combination with a lysosomotropic agent, such as chloroquine. The compounds were active against a variety of cancer cells such as HeLa (cervical cancer cell), A549 (lung carcinoma), and PDX-2 or PDX-3 (lung adenocarcinoma). The invention also relates to compositions and methods for prevention and/or treatment of cancer diseases using the new bis-triazole 2,4,6-triarylpyridines compounds.