IRE1α Endoribonuclease Inhibitors With Pyrido-Pyrimidinone Scaffolds
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Solution Overview
Problem
There is a need for potent and selective inhibitors targeting IRE1α to treat IRE1-related diseases or disorders, including cancer, autoimmune, neurodegenerative, fibrotic, and metabolic disorders, as existing inhibitors may not effectively block the endoribonuclease activity of IRE1α and have unsuitable pharmacological properties.
Innovation Solution
Development of pyrido-pyrimidinone and pteridinone compounds that specifically target the IRE1α enzyme, modulating its activity and providing therapeutic benefits.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing inhibitors are used to target IRE1α, then some level of inhibition is achieved, but the endoribonuclease activity is not effectively blocked and pharmacological properties are unsuitable
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structures (pyrido-pyrimidinone and pteridinone cores with various substituents at positions R1-R11) to optimize binding affinity and selectivity for IRE1α. This involves changing molecular parameters such as substituent types, positions, and configurations to achieve potent and selective inhibition of IRE1α endoribonuclease activity while maintaining suitable pharmacological properties
Solution Approach 2:
The patent segments the inhibitor molecule into distinct functional regions: a core pyrido-pyrimidinone or pteridinone structure with specific substitution patterns. The molecule is divided into regions that interact with different parts of the IRE1α binding site, allowing independent optimization of each region's contribution to binding affinity and selectivity
2Object-affected harmful factors
If IRE1α activity is blocked to treat cancer, then tumor cell growth is inhibited, but the complexity of achieving selective inhibition increases
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific local chemical features (substituents at R1-R11 positions) that interact with unique aspects of the IRE1α binding site. This localized optimization of molecular features enables selective inhibition of IRE1α over other kinases while maintaining the ability to block endoribonuclease activity and induce apoptosis in tumor cells
Data Source
AI summary
Described herein are pyrido-pyrimidinone and pteridinone compounds or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods treating cancer, alone and in combination with other therapeutic agents.