DOT1L Degrader Design for Targeted Ubiquitin-Proteasome Clearance
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Solution Overview
Problem
There is a need for compounds that can effectively target and promote the degradation of proteins associated with proliferative diseases and cancers, such as DOT1L, by utilizing the cellular machinery of ubiquitination and proteasome degradation.
Innovation Solution
Development of compounds comprising an E3 ubiquitin ligase binding moiety, like lenalidomide or thalidomide, which bind to the target protein DOT1L, inducing its ubiquitination and subsequent proteasome degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional inhibitors of DOT1L are used, then DOT1L activity is blocked, but the protein remains present in the cell and continues to exert its effects
Solution Approach 1:
The patent converts the natural function of DOT1L (which promotes cell survival and proliferation) into a therapeutic benefit by engineering a degrader that exploits the cell's own ubiquitin-proteasome degradation system to eliminate DOT1L, thereby turning the protein's functional activity into a pathway for its removal
Solution Approach 2:
The patent introduces an intermediary mechanism (ubiquitination) between the degrader compound and DOT1L degradation. The compound induces ubiquitin attachment to DOT1L, which then directs the protein to the proteasome for degradation, using the cell's existing degradation machinery as an intermediary system
2Productivity
If DOT1L is inhibited but not degraded, then enzyme activity is reduced, but the protein can be synthesized again and maintain pathological functions
Solution Approach 1:
The patent applies preliminary action by inducing ubiquitination of DOT1L before degradation occurs. The degrader compound first modifies DOT1L through ubiquitin attachment, marking it for subsequent proteasomal degradation, thereby preventing the protein from returning to its active state
Solution Approach 2:
The patent changes the stability parameter of DOT1L by inducing ubiquitination, which fundamentally alters the protein's fate from being stable and reusable to being marked for degradation. This parameter change ensures the protein cannot simply be re-synthesized into an active form without first being degraded
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
These compounds provide a therapeutic approach to treat and prevent diseases associated with DOT1L, including cancers, by promoting the targeted degradation of DOT1L through the ubiquitin-proteasome pathway.
Implementation Method 1
The disclosed compounds are used for assessing the activity of DOT1L and for identifying inhibitors of DOT1L. The recognition that is targeting a selected protein, and the use of an E3 ubiquitin ligase binding moiety, leads to the ubiquitination of the selected target protein DOT1L, thereby resulting in proteasome degradation of the target protein.
Data Source
Figure 1~2A
Figure 2B~2C
Figure 3
AI summary
Provided herein are bifunctional compounds with a moiety (e.g., lenalidomide, thalidomide) that is a binder of an E3 ubiquitin ligase (e.g., Cereblon) and another moiety that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one component of the bifunctional compound is a binder of an E3 ubiquitin ligase (e.g., lenalidomide, thalidomide) and another component of the compound is a binder of the target protein DOT1L in a subject.