Pteridinone Compounds Target WFS1 to Trigger Cancer Cell Death
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Solution Overview
Problem
Current treatments for cellular proliferative disorders, such as cancer, are limited and there is a need for additional therapeutic options to address these conditions effectively.
Innovation Solution
Compounds of Formula I, or their pharmaceutically acceptable salts, target the Wolframin (WFS1) protein to induce calcium release from the endoplasmic reticulum, triggering ER stress and the unfolded protein response, leading to cell death in cancer cells, particularly those with WFS1 overexpression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current treatments for cellular proliferative disorders are used, then existing therapeutic options are maintained, but treatment effectiveness is limited and additional therapeutic options are needed
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (Formula I) that target the WFS1 protein's calcium channel function. By modifying chemical parameters (molecular structure, substituents R1-R6, ring systems), the invention creates novel therapeutic agents with enhanced efficacy against cellular proliferative disorders, directly addressing the need for additional therapeutic options with improved treatment effectiveness
Solution Approach 2:
The patent uses the WFS1 protein as an intermediary target between the administered compounds and the pathological effects in cellular proliferative disorders. The compounds bind to WFS1's calcium channel, modulating calcium release from the endoplasmic reticulum, which serves as the mediating mechanism to achieve therapeutic effects against cancer and other proliferative disorders
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
These compounds demonstrate pronounced efficacy in multiple cell-line-derived and patient-derived xenograft models, resulting in complete and durable regression of cancers like non-small cell lung cancer, myeloma, hepatocellular carcinoma, and breast cancer, with enhanced inhibition of cell viability.
Implementation Method 1
target the Wolframin (WFS1) protein to induce calcium release from the endoplasmic reticulum
Implementation Method 2
triggering ER stress and the unfolded protein response
Implementation Method 3
triggering ER stress and the unfolded protein response
Data Source
AI summary
The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof for treating cellular proliferative disorders (e.g., cancer).