CELMoD Compounds Degrade WEE1 Kinase via Cereblon
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Solution Overview
Problem
Current cancer therapies often rely on inducing DNA damage and replication stress, which can lead to resistance and limited therapeutic windows. There is a need for targeted approaches that specifically degrade WEE1, a key protein involved in cell cycle checkpoints, to enhance antitumor activity.
Innovation Solution
Development of CELMoD compounds that induce Cereblon-mediated ubiquitination and degradation of WEE1, potentially used as single agents or in combination with DNA damaging agents to synergistically target cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DNA damaging agents are used to induce replication stress, then antitumor activity is enhanced, but resistance develops and therapeutic window is limited
Solution Approach 1:
The patent introduces CELMoD compounds as intermediary molecules that mediate between the Cereblon E3 ligase complex and WEE1 target protein. These compounds create a new molecular interface on Cereblon that recruits WEE1 for polyubiquitination and degradation, providing a targeted mechanism to reduce WEE1 levels without the broad DNA damage effects of traditional chemotherapies, thereby reducing resistance development and expanding therapeutic window.
Solution Approach 2:
The patent replaces the mechanical/chemical DNA damage mechanism with a protein degradation mechanism. Instead of using DNA damaging agents that cause replication stress and mutate cancer cells, the invention uses CELMoD compounds to induce selective degradation of WEE1 protein through the Cereblon E3 ligase system, achieving antitumor activity through protein level reduction rather than DNA damage, thus avoiding resistance mechanisms associated with DNA damage.
2Reliability
If WEE1 is targeted for degradation, then cell cycle checkpoints are disrupted, but off-target effects may occur
Solution Approach 1:
The patent applies local quality by creating a specific molecular interface on the Cereblon protein surface through CELMoD compound binding. This interface is locally created only where the compound binds to Cereblon, and it specifically recruits WEE1 for degradation. The specificity is achieved through the precise molecular structure of the CELMoD compound that creates a unique binding interface, ensuring that only WEE1 is recruited and degraded, not other proteins, thus minimizing off-target effects.
Solution Approach 2:
The patent changes the parameter of protein stability by inducing degradation of WEE1. The CELMoD compound modifies the stability parameter of WEE1 by creating a new ubiquitination pathway that leads to its degradation. This parameter change is achieved through the specific molecular interaction between the compound and Cereblon, which then recruits WEE1 for degradation, providing a controlled and specific way to reduce WEE1 levels without affecting other stable proteins.
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 CELMoD compounds effectively reduce WEE1 kinase protein levels, leading to broad antitumor activity and potentially offering a favorable therapeutic window by targeting cancer cells' reliance on cell cycle checkpoints.
Implementation Method 1
CELMoD compounds that induce the Cereblon-mediated ubiquitination and degradation of WEE1
Implementation Method 2
The ubiquitin tagged proteins are then trafficked to and subsequently degraded by the 26S proteasome
Data Source
AI summary
Provided herein are compounds and compositions thereof that reduce WEE1 kinase protein levels. In some embodiments, the compounds and compositions are provided for treatment WEE1 associated diseases such as cancer.