Redox-Cycling Senolytic Compounds for Selective Cell Elimination
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Solution Overview
Problem
Existing senolytic compounds primarily target anti-apoptotic proteins of the Bcl-2 family, but the underlying mechanisms of other potential senolytics are not fully understood, and there is a need for compounds that can selectively eliminate senescent cells across various medical fields, including cancer and age-related diseases.
Innovation Solution
Development of novel compounds with a 3-substituted pyrimido-[5,6-e]-1,2,4-triazine-5,7-dione core structure that undergo a redox cycle to produce hydrogen peroxide, selectively targeting and killing senescent cells through a redox mechanism, utilizing the metabolic alterations of these cells to generate high concentrations of hydrogen peroxide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If compounds targeting anti-apoptotic proteins of the Bcl-2 family are used as senolytics, then senescent cell elimination is achieved, but the mechanism is limited to specific protein targets and may not cover all senescent cell types
Solution Approach 1:
The patent changes the mechanism parameter from direct protein targeting to redox cycle-based hydrogen peroxide generation. The compounds undergo redox cycling to produce H2O2, which selectively kills senescent cells through oxidative stress. This parameter change enables pan-senolytic activity across different senescent cell types without requiring multiple specific protein targets, thereby improving versatility while simplifying the underlying mechanism.
2Reliability
If new senolytic compounds are developed to address diverse disease models, then therapeutic effectiveness is improved, but compound structure complexity increases
Solution Approach 1:
The patent applies universality by developing a single core chemical structure (pyrimido-triazine-5,7-dione) that serves multiple functions: it undergoes redox cycling to generate hydrogen peroxide, selectively targets senescent cells, and can be applied across diverse disease models including cancer and age-related conditions. This universal structure simplifies compound development while maintaining high senolytic efficacy across different applications.
3Object-affected harmful factors
If the redox cycle mechanism is utilized to generate hydrogen peroxide, then selective killing of senescent cells is achieved, but the mechanism requires metabolic alterations in senescent cells
Solution Approach 1:
The patent converts the harmful metabolic alterations in senescent cells (such as increased oxidative stress and altered redox state) into a beneficial selective killing mechanism. The compounds exploit these metabolic changes by undergoing redox cycling that generates hydrogen peroxide specifically in senescent cells, which then die from oxidative stress. Thus, the harmful metabolic alterations are transformed into the basis for selective therapeutic effect.
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 compounds effectively eliminate senescent cells by generating hydrogen peroxide, offering a pan-senolytic solution that addresses the challenges of senescent cell persistence in diseases, particularly in cancer and age-related conditions.
Implementation Method 1
compounds with a 3-substituted pyrimido-[5,6-e]-1,2,4-triazine-5,7-dione core structure that undergo a redox cycle to produce hydrogen peroxide
Implementation Method 2
undergo a redox cycle to produce hydrogen peroxide, selectively targeting and killing senescent cells through a redox mechanism
Implementation Method 3
generating hydrogen peroxide, offering a pan-senolytic solution that addresses the challenges of senescent cell persistence
Data Source
Figure 1A
Figure 1B
Figure 2A~2B
AI summary
The present invention relates, amongst others, to the use of a compound according to general formula (I), a derivative of such compound according to any of general formulae (II), (III), or (IV), or a pharmaceutically acceptable salt or hydrate of such compound or derivative as senolytic. The invention further relates to selected compounds according to general formula (I), (II), (III), or (IV).