Multikinase PROTAC Degraders for Broad Kinase Target Identification
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Solution Overview
Problem
Existing kinase inhibitors are limited in their ability to target multiple kinases simultaneously, and there is a challenge in identifying specific kinase drug targets and designing selective degraders for drug-resistant cells.
Innovation Solution
Development of multikinase degraders, specifically heterobifunctional compounds (PROTACs) with a ubiquitin E3 ligase ligand binding moiety and a promiscuous kinase ligand, which facilitate the degradation of multiple kinases, enabling identification of target kinases in cell-based assays and potential therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If promiscuous kinase binder warheads are used, then kinase binding capability is improved, but generality and applicability to multiple kinases deteriorates
Solution Approach 1:
The patent applies universality by designing a heterobifunctional compound where one moiety (thalidomide or analog) serves as a universal recruiter for cereblon E3 ligase across multiple kinase targets, while the other moiety provides kinase-specific binding. This allows a single compound framework to degrade multiple different kinases (CHK1, CHK2, ATM, ATR, etc.) by leveraging the universal cereblon recruitment capability combined with variable kinase-binding groups.
Solution Approach 2:
The compound is segmented into distinct functional moieties: a cereblon-recruiting thalidomide moiety and a kinase-binding moiety. This segmentation allows independent optimization of each function - the thalidomide portion ensures universal E3 ligase recruitment while the kinase-binding portion can be tailored to specific kinase targets, resolving the contradiction between reliable binding and broad applicability.
2Measurement precision
If selective kinase degraders are designed for specific targets, then degradation specificity is improved, but ability to treat drug-resistant cells through multikinase degradation deteriorates
Solution Approach 1:
The patent employs dynamic design by creating a platform where the kinase-binding moiety can be adjusted or selected based on the specific therapeutic need. The core thalidomide structure remains constant for universal cereblon recruitment, while the kinase-binding portion can be modified to target different kinases or combinations thereof, allowing adaptation to various drug-resistant cell types while maintaining degradation specificity for the intended target.
3Productivity
If heterobifunctional compounds with ubiquitin E3 ligase ligand are used, then degradation efficiency is improved, but compound complexity increases
Solution Approach 1:
The patent uses cereblon E3 ligase as an intermediary to mediate the degradation process. The thalidomide moiety recruits this intermediary protein, which then facilitates the ubiquitination and degradation of the target kinase. This intermediary approach allows efficient degradation without requiring the compound itself to directly catalyze degradation, thereby improving productivity while managing complexity through biological mediation.
Data Source
AI summary
Multikinase degraders described herein contain on one end a Von Hippel-Lindau (VHL) E3 ligase ligand or cereblon E3 ligase recruiter moiety, which bind to the VHL or cereblon E3 ubiquitin ligase (defined as a ubiquitin ligand binding moiety or ULM group), respectively, and on the other end a promiscuous kinase ligand that binds a target protein kinase (defined as a protein/polypeptide targeting moiety or PTM group), such that the target protein is in close proximity to the ubiquitin ligase. This leads to the ubiquitination and subsequent degradation (and inhibition) of the target protein. Specific present multikinase degraders as shown bind about 360 out of 400 tested kinases, showing that they are much more general kinase binders and degraders than any previously reported.