Phenylallylidene Keap1 Modulators for Brain-Penetrant Nrf2 Activation
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Solution Overview
Problem
Current treatments for cancer and inflammatory conditions, particularly those targeting the Nrf2/KEAP1 complex, face challenges in efficacy due to limitations in binding affinity, stability, and solubility, and lack effective compounds that can penetrate the blood-brain barrier to target brain cells and tumors.
Innovation Solution
Development of phenylallylidene compounds that bind to cysteine residues of the Keap1 protein, promoting ubiquitination and proteasomal degradation of KEAP1, thereby activating the Nrf2 pathway, and offering improved pharmacological properties such as potency, stability, and solubility, including the use of PROTACs as ubiquitin ligase recruiting moieties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known compound obtusaquinone (OBT) is used to target Nrf2/KEAP1 complex, then binding affinity to KEAP1 is achieved, but pharmacological properties such as stability and solubility are insufficient
Solution Approach 1:
The patent modifies the chemical structure of obtusaquinone by changing parameters such as adding fluorine atoms, modifying aromatic rings, and adjusting side chains to improve stability and solubility while maintaining binding affinity to KEAP1 cysteine residues
Solution Approach 2:
The patent creates hybrid compounds that combine the core obtusaquinone structure with additional functional groups and moieties to achieve both high binding affinity and improved pharmacological properties including enhanced stability and solubility
2Reliability
If known compound obtusaquinone (OBT) is used to activate Nrf2 pathway, then therapeutic effect is achieved, but solubility is insufficient for effective delivery
Solution Approach 1:
The patent introduces solubility-enhancing modifications including hydroxyl groups, carboxylic acid groups, and polar substituents to the obtusaquinone core structure, increasing aqueous solubility while preserving the ability to bind KEAP1 and activate Nrf2 pathway
Solution Approach 2:
The patent employs solubility-enhancing functional groups as intermediaries that improve drug solubility without interfering with the primary interaction between the compound and KEAP1 cysteine residues
3Reliability
If current treatments are used to target Nrf2/KEAP1 complex, then general cancer treatment is achieved, but penetration of blood-brain barrier is insufficient for brain tumor targeting
Solution Approach 1:
The patent modifies lipophilicity and molecular size parameters of the compounds to optimize blood-brain barrier penetration while maintaining the ability to bind KEAP1 and activate Nrf2 pathway in brain tissue
Solution Approach 2:
The patent creates compounds with dynamic properties that allow them to interact with the blood-brain barrier transport mechanisms and achieve effective delivery to brain tumors
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 target brain cells and tumors by activating the Nrf2 pathway, demonstrating enhanced binding affinity, stability, and solubility, providing therapeutic benefits for conditions like cancer and neurodegenerative diseases.
Implementation Method 1
The compounds described herein are capable of binding to cysteine residues and show affinity to cysteine-rich Keap1 protein
Implementation Method 2
The compounds are capable to penetrate the blood-brain barrier and functionally target brain cells and brain tumors
Data Source
AI summary
The present application provides methods and compounds of modulating Nrf2 pathway. Methods for treating cancer and neurodegenerative conditions are also provided.