ERK5 PROTAC Degraders Resolve Paradoxical Kinase Activation
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Solution Overview
Problem
Current approaches to reduce ERK5 kinase activity, such as kinase inhibition, have limitations including paradoxical activation, non-specificity, and failure to inhibit all aspects of ERK5 function, particularly its non-kinase dependent functions.
Innovation Solution
Development of compounds that degrade ERK5 kinase, allowing for the reduction of ERK5 activity through proteolysis targeting chimera (PROTAC) technology, which targets and degrades ERK5, potentially addressing all aspects of its function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If kinase inhibition is used to reduce ERK5 kinase activity, then ERK5 kinase activity is reduced, but paradoxical activation of ERK5 occurs and non-specific effects on other proteins (e.g., BRD4) are observed
Solution Approach 1:
The invention extracts and eliminates the harmful paradoxical activation and non-specific effects by using a degradation-based approach rather than inhibition. The PROTAC compound selectively targets ERK5 for degradation, removing the protein entirely from the system rather than attempting to inhibit its activity, thereby avoiding the harmful side effects associated with kinase inhibition
Solution Approach 2:
The invention changes the fundamental parameter of ERK5 control from activity modulation (inhibition) to protein abundance reduction (degradation). By targeting ERK5 for proteasomal degradation, the system achieves complete elimination of ERK5 function including both kinase-dependent and kinase-independent functions, avoiding the paradoxical activation seen with traditional inhibitors
2Reliability
If kinase inhibitors are used to reduce ERK5 activity, then some ERK5 kinase function is inhibited, but all aspects of ERK5 function (including non-kinase dependent functions) are not inhibited
Solution Approach 1:
The PROTAC compound provides universal inhibition of all ERK5 functions by degrading the ERK5 protein itself. Since the degradation targets the protein rather than specifically its kinase domain, both kinase-dependent and kinase-independent functions are simultaneously eliminated, achieving comprehensive functional inhibition that kinase inhibitors cannot accomplish
3Reliability
If ERK5 kinase inhibitors are used, then kinase activity is reduced, but the strong anti-cancer phenotype of ERK5 loss (genetic/siRNA) cannot be fully recapitulated
Solution Approach 1:
The PROTAC approach copies the complete effect of genetic ERK5 loss by degrading ERK5 protein to undetectable levels, thereby recapitulating the strong anti-cancer phenotype observed in genetic models. This degradation-based strategy mirrors the complete absence of ERK5 in genetic knockouts, unlike partial inhibition by kinase inhibitors
Data Source
AI summary
The present invention relates to compounds of Formula (I) shown below that function as degraders of ERK5 kinase:wherein R1, R2, R3, X1, L and Q are each as defined herein. The compounds are useful for the treatment of: a fibrotic disease; a proliferative condition, e.g. cancer; diabetes; pain; and/or a central nervous system (CNS) disorder.