HDAC6 Degrader Composition Using E3 Ligase Recruitment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current HDAC inhibitors are non-selective, leading to significant toxicity and limited efficacy in treating diseases like cancer, while HDAC6, primarily located in the cytoplasm, is aberrantly active and overexpressed in various diseases, necessitating a selective inhibitor.
Innovation Solution
Development of compounds comprising a HDAC6-selective inhibitor covalently bonded to a linker and an E3 ubiquitin ligase ligand, targeting HDAC6 for degradation through the body's natural protein disposal system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective HDAC inhibitors are used, then broad HDAC activity is inhibited, but significant toxicity occurs and efficacy is limited
Solution Approach 1:
The patent segments the HDAC inhibitor class into selective HDAC6 inhibitors, separating the desired therapeutic effect from the harmful off-target effects. By designing inhibitors that specifically target HDAC6 rather than all HDACs, the patent achieves reliable efficacy against diseases like cancer while avoiding the significant toxicity associated with non-selective HDAC inhibition.
2Object-affected harmful factors
If HDAC6 selective inhibitors are developed, then toxicity is reduced, but the compounds need to achieve potent degradation of HDAC6 protein
Solution Approach 1:
The patent employs PROTAC molecules as intermediaries that facilitate the degradation of HDAC6. These heterobifunctional compounds contain an HDAC6 inhibitor portion that binds to HDAC6, a linker, and an E3 ligase ligand portion that recruits the ubiquitin-proteasome system. This intermediary mechanism enables potent and selective degradation of HDAC6 while avoiding the toxicity of non-selective inhibition.
Solution Approach 2:
The patent changes the functional parameter from simple inhibition to catalytic degradation. By designing PROTACs that induce ubiquitination and proteasomal degradation, the system achieves amplification of the therapeutic effect - a single PROTAC molecule can lead to the degradation of multiple HDAC6 molecules, thereby achieving high degradation potency with reduced toxicity.
3Reliability
If PROTAC molecules are designed with HDAC6 inhibitor and E3 ligase ligand portions, then selective HDAC6 degradation is achieved, but the molecular complexity increases
Solution Approach 1:
The PROTAC molecule is segmented into distinct functional portions: an HDAC6 inhibitor portion (such as hydroxamic acid derivatives), a linker (such as p-aminobenzoyl glycine or p-aminobenzoyl propionic acid), and an E3 ligase ligand portion (such as thalidomide or lenalidomide). This segmentation allows each component to perform its specific function while maintaining overall selectivity for HDAC6 degradation.
Solution Approach 2:
The patent creates composite PROTAC molecules by combining different chemical moieties with complementary functions. The HDAC6 inhibitor portion provides target binding, the linker provides structural connectivity and spatial orientation, and the E3 ligase ligand portion provides recruitment of the degradation machinery. This composite structure achieves high selectivity and potency despite the increased molecular complexity.
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 selectively degrade HDAC6, reducing neoplastic cell growth and toxicity, offering potential therapeutic benefits for diseases such as cancer, neurodegenerative diseases, and autoimmune disorders.
Implementation Method 1
targeting HDAC6 for degradation through the body's natural protein disposal system
Implementation Method 2
engage the body's own natural protein disposal system to destroy the pathogenic protein
Data Source
AI summary
Histone deacetylase (“HDAC”)-selective inhibitors covalently bonded to a linker covalently bonded to an E3 ubiquitin ligase ligand, and salts thereof; pharmaceutical compositions containing them; methods of using the composition to inhibit neoplastic cell growth in mammals, including humans.