Selective Hydroxamic Acid HDAC6 Inhibitors for Lower Toxicity
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Solution Overview
Problem
Current HDAC inhibitors are non-selective, leading to side effects and dose-limited toxicity due to their poor specificity, particularly for HDAC6, which is associated with cancer and neurodegenerative disorders.
Innovation Solution
Development of novel hydroxamic acid compounds that act as selective HDAC6 inhibitors, offering high potency and safety for treating HDAC6-associated conditions such as cancer and neurodegenerative disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pan-HDAC inhibitors are used, then HDAC activity is inhibited, but side effects and dose-limited toxicity occur due to poor selectivity
Solution Approach 1:
The patent applies local quality by designing HDAC inhibitors with specific molecular structures (hydroxamic acid compounds with particular substituent patterns) that confer selective binding affinity to HDAC6 over other HDAC isoforms. This localized specificity at the molecular level enables the inhibitor to target HDAC6 functionally while sparing other HDACs, thereby reducing off-target side effects and toxicities associated with non-selective pan-HDAC inhibitors.
2Adaptability or versatility
If non-selective HDAC inhibitors are used, then broad HDAC inhibition is achieved, but selectivity for HDAC6 is lost
Solution Approach 1:
The patent employs parameter changes by systematically varying molecular parameters of the hydroxamic acid compounds, including substituent types (e.g., aryl, heteroaryl groups), positional arrangements, and steric configurations. These parameter modifications optimize the compound's interaction with HDAC6's active site, achieving high selectivity through precise molecular fitting while maintaining the hydroxamic acid core structure necessary for HDAC inhibition.
Data Source
AI summary
Disclosed herein are hydroxamic acid compounds. Also disclosed is a method of using the hydroxamic acid compounds of the present disclosure for treating a condition associated with histone deacetylase 6.