Piperidine-2,6-dione Derivative for CRBN Binding
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Solution Overview
Problem
Thalidomide derivatives face challenges due to severe side effects while retaining their physiological activity, necessitating the development of a novel piperidine-2,6-dione compound for treating leprosy, chronic graft versus host disease, inflammatory diseases, and cancer.
Innovation Solution
A piperidine-2,6-dione derivative is synthesized, specifically reacting compounds represented by Chemical Formula 1 with sodium nitrite to produce a compound with pharmaceutical acceptability, which binds to the CRBN protein for target protein degradation, thereby treating the mentioned diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If thalidomide is used to treat inflammatory diseases and cancer, then therapeutic effect is improved, but severe side effects including teratogenicity occur
Solution Approach 1:
The patent divides the thalidomide molecule into separate components: a glutarimide ring (core structure) and a phthalimide substituent. By separating these functional elements, the invention creates analogs that retain the desired anti-inflammatory and anti-cancer activities while reducing or eliminating the teratogenic side effects associated with the original thalidomide structure.
Solution Approach 2:
The patent modifies specific local regions of the thalidomide molecule by replacing the phthalimide group with various substituted phenylisoxazole structures. These localized structural changes at the R1 and R2 positions allow optimization of therapeutic properties while minimizing harmful effects, demonstrating that specific local modifications can improve the risk-benefit ratio.
2Object-affected harmful factors
If thalidomide derivatives are developed to reduce side effects, then safety is improved, but physiological activity may be compromised
Solution Approach 1:
The patent systematically varies chemical parameters of the glutarimide analogs, including substituent types (R1, R2, R3, R4), substituent positions, and molecular configuration. By changing these chemical parameters while maintaining the core glutarimide structure, the invention identifies compounds that preserve essential physiological activities (CRBN binding, immunomodulation) while reducing teratogenicity.
Solution Approach 2:
The patent introduces intermediate structures (substituted phenylisoxazole groups) that serve as mediators between the glutarimide core and the desired therapeutic effects. These intermediary groups modulate the molecule's interaction with target proteins like CRBN, allowing retention of beneficial activities while reducing harmful effects.
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 compound effectively binds to the CRBN protein, degrading Ikaros/Aiolos and GSPT1, demonstrating potential in treating leprosy, chronic graft versus host disease, inflammatory diseases, and cancer with reduced side effects.
Implementation Method 1
binds to the CRBN protein for target protein degradation
Data Source
Figure 1~2
AI summary
The present disclosure relates to a novel piperidine-2,6-dione derivative and a use thereof and, more specifically, to a piperidine-2,6-dione derivative compound having a structure of a thalidomide analog. A compound of chemical formula 1 according to the present disclosure specifically binds with CRBN protein, and is involved in functions thereof. Therefore, the compound of the present disclosure can be favorably used in the prevention or treatment of leprosy, chronic graft versus host disease, an inflammatory disease, or cancer, which are caused by actions of CRBN protein.