ERK1/2 Docking-Site Modulators for Airway Remodeling Control
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Solution Overview
Problem
Current kinase inhibitors targeting ATP binding sites for treating pulmonary diseases like asthma face issues with acquired drug resistance and toxicity, while upregulated ERK1/2 activity contributes to asthma pathogenesis through airway remodeling.
Innovation Solution
Development of function-selective ERK1/2 modulators, specifically targeting the ERK1/2 substrate docking site to inhibit AP-1 activity, reducing ASM and LF cell hyperplasia and ECM hypersecretion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ATP binding site kinase inhibitors are used to treat pulmonary diseases, then kinase activity is blocked, but acquired drug resistance and toxicity occur
Solution Approach 1:
The patent extracts and targets only the specific substrate docking site interaction of ERK1/2 with AP-1 complex proteins, rather than blocking the general ATP binding site. This selective extraction of the pathogenic signaling pathway (ERK1/2-mediated AP-1 activity) allows inhibition of disease-causing effects while preserving other kinase functions, thereby reducing drug resistance and toxicity
Solution Approach 2:
The invention applies local quality by creating a function-selective inhibitor that specifically targets the substrate docking site of ERK1/2 involved in AP-1 complex interactions. This localized inhibition at the specific protein-protein interaction interface (rather than general kinase activity blockade) enables selective suppression of pathogenic signaling while maintaining other physiological kinase functions
2Reliability
If ERK1/2 activity is inhibited to address airway remodeling, then ASM and LF cell hyperplasia is reduced, but selectivity of inhibition must be maintained
Solution Approach 1:
The compound selectively inhibits ERK1/2 substrate docking site interactions with AP-1 complex proteins while preserving other kinase functions. This local quality approach targets specifically the pathogenic ERK1/2-mediated airway remodeling pathway in ASM and LF cells, achieving therapeutic efficacy while maintaining selectivity and avoiding broad kinase suppression
Solution Approach 2:
The invention uses the substrate docking site as an intermediary target - rather than directly blocking ATP binding or catalytic activity, the compound interferes with the protein-protein interaction interface between ERK1/2 and AP-1 complex. This intermediary approach provides function-selective inhibition that achieves desired therapeutic effects with improved selectivity
Data Source
AI summary
Modulators of extracellular signal-regulated kinase, pharmaceutical compositions thereof, and uses of the compound and pharmaceutical compositions thereof for treating cancer and pulmonary diseases are disclosed.