Bivalent ENL Degrader for Leukemia via Proteasomal Pathway
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Solution Overview
Problem
Current ENL YEATS domain inhibitors, such as SGC-iMLLT, are ineffective in inhibiting the growth of ENL-dependent MLL-rearranged leukemia cells, despite blocking the interaction between the ENL YEATS domain and acetylated histone H3, highlighting the need for a new therapeutic strategy that can pharmacologically degrade ENL protein in cells and tumors.
Innovation Solution
Development of bivalent compounds comprising an ENL ligand conjugated to a degradation/disruption tag, specifically designed to recruit E3 ubiquitin ligases and induce ENL protein degradation, mimicking protein misfolding to target ENL for proteasomal degradation, thereby phenocopying the effects of ENL knockout.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional ENL YEATS domain inhibitors (e.g., SGC-iMLLT) are used to block the interaction between ENL YEATS domain and acetylated histone H3, then the binding affinity to ENL YEATS domain is improved (nanomolar level), but the therapeutic efficacy in inhibiting leukemia cell growth deteriorates (largely ineffective in cells)
Solution Approach 1:
The compound is divided into two functional modules: an ENL YEATS domain binder (e.g., SGC-iMLLT) and a separate degradation tag (e.g., VHL ligand). This segmentation allows each module to independently perform its function - binding to ENL and recruiting the degradation machinery, respectively - thereby achieving both high binding affinity and therapeutic efficacy that neither module could achieve alone.
Solution Approach 2:
The patent merges the ENL binder and degradation tag into a single bivalent compound through a linker. This combination enables the compound to simultaneously bind to ENL YEATS domain and recruit VHL E3 ubiquitin ligase, thereby coupling high-affinity binding with protein degradation functionality to overcome the limitations of traditional inhibitors.
2Reliability
If ENL protein levels are maintained to preserve chromatin reader function, then transcriptional co-regulation is preserved, but leukemia progression is promoted; conversely, if ENL is depleted to inhibit oncogenic gene expression, then leukemia progression is suppressed, but normal transcriptional regulation may be affected
Solution Approach 1:
The bivalent compound acts as an intermediary that recruits VHL E3 ubiquitin ligase to the ENL YEATS domain complex. This intermediary mechanism enables selective degradation of ENL protein through the ubiquitin-proteasome pathway, providing controlled suppression of oncogenic functions while allowing potential preservation of normal physiological roles through regulated degradation.
Solution Approach 2:
The invention changes the parameter of ENL protein stability by introducing a degradation tag that alters the half-life of ENL protein. By controlling the rate of protein degradation rather than completely eliminating ENL function, the system can suppress oncogenic gene expression while potentially allowing normal transcriptional regulation to persist at reduced levels.
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 bivalent compounds effectively reduce ENL protein levels and inhibit the proliferation of ENL-dependent leukemia cells in vitro and in vivo, offering a more potent therapeutic approach than traditional ENL inhibitors by directly degrading ENL protein.
Implementation Method 1
induce ENL protein degradation, mimicking protein misfolding to target ENL for proteasomal degradation
Data Source
AI summary
Disclosed are Eleven-Nineteen Leukemia (ENL) degradation/disruption compounds including a ENL ligand, a degradation/disruption tag and a linker, and methods for use of such compounds in the treatment of ENL-mediated diseases.