Combination Therapy Targeting Super-Enhancer Components
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Solution Overview
Problem
Current methods are inadequate for effectively targeting and treating diseases mediated by super-enhancers, which are dysregulated in various diseases including cancer, as they often require more profound inhibition of super-enhancer components compared to typical enhancer elements.
Innovation Solution
Administration of a combination of therapeutic agents including cyclin-dependent kinase inhibitors, bromodomain inhibitors, histone methyltransferase inhibitors, histone deacetylase inhibitors, and histone demethylase inhibitors to disrupt super-enhancer function, with specific examples being alvocidib, JQ1, OTX015, and IBET762, which are used alone or in combination to target multiple components of the super-enhancer complex.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single agent therapy is used to target super-enhancer components, then treatment simplicity is maintained, but therapeutic efficacy is insufficient
Solution Approach 1:
The patent combines multiple therapeutic agents targeting different super-enhancer components (BET proteins, CDK9, HDACs, HMTs, HDMs) into a single treatment regimen. This merging of multiple inhibition mechanisms achieves synergistic effects that profoundly disrupt super-enhancer function and drive oncogene degradation, resolving the contradiction between treatment simplicity and therapeutic efficacy.
Solution Approach 2:
The treatment uses a composite approach by combining agents with different mechanisms of action (bromodomain inhibition, cyclin-dependent kinase inhibition, histone deacetylase inhibition, histone methyltransferase inhibition, histone demethylase inhibition). This composite strategy targets multiple components of the super-enhancer complex simultaneously, achieving profound therapeutic effects while maintaining a unified treatment protocol.
2Reliability
If inhibition of super-enhancer components is intensified to achieve therapeutic effect, then disease treatment efficacy improves, but off-target effects on typical enhancers increase
Solution Approach 1:
The patent exploits the local quality difference between super-enhancers and typical enhancers by targeting components that are specifically enriched at super-enhancers. The combination therapy preferentially affects super-enhancer regions where these components are densely concentrated, while having minimal impact on typical enhancers with lower component density, thus achieving selective inhibition with reduced off-target effects.
Solution Approach 2:
The treatment employs partial inhibition strategies where each individual agent at moderate doses targets specific super-enhancer components without completely shutting down all enhancer activity. The combination of multiple partial inhibitions achieves profound overall suppression of super-enhancer function while allowing typical enhancers to maintain sufficient activity for normal cellular functions.
Data Source
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AI summary
Methods for targeting super enhancers by administration of two or more therapeutic agents are provided. The methods are useful for treatment of various super-enhancer-mediated diseases and conditions, such as cancer. Compositions comprising the two or more therapeutic agents are also provided. In brief, embodiments of the present invention provide methods for treatment of disease involving administration of inhibitors of two of more components of super-enhancers.