p38 MAP Kinase Inhibitors via SMN Complex Relocalization Testing

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Solution Overview

Problem

Current inhibitors targeting p38 mitogen-activated protein kinase (MAPK) face challenges in clinical development due to dose-limiting secondary effects and limited therapeutic index, despite their potential in treating inflammatory and cancer-related conditions.

Innovation Solution

Development of compounds with specific structures, such as those according to Formula (I), which inhibit p38 MAPK activity by assessing the relocalization of the SMN complex component from the cytoplasm to the nucleus, and methods for testing these compounds using protein synthesis inhibitors and activators of p38 MAPK activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If p38 MAPK inhibitors are used to treat inflammatory and cancer-related conditions, then therapeutic effectiveness is improved, but dose-limiting secondary effects increase

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoiddose-limiting secondary effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (Formula I with particular R1, R2, X1, X2 configurations) that target p38 MAPK with enhanced selectivity. This localized structural optimization allows the drug to interact preferentially with the p38 isoform rather than other MAPK family members, improving therapeutic effectiveness while reducing off-target secondary effects that limit dosing

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If p38 MAPK inhibitors are developed to achieve broader therapeutic index, then treatment window is improved, but selectivity and specificity challenges arise

Engineering Contradiction:

Improvetherapeutic indexVSAvoidselectivity and specificity

Core Design Contradiction:

Adaptability or versatilityVSManufacturing precision

Solution Approach 1:

The patent employs parameter changes by systematically varying molecular parameters in the compound structure (different substituents for R1 and R2, different heteroatoms for X1 and X2) to optimize the balance between therapeutic index and selectivity. Each structural parameter is tuned to achieve optimal binding affinity for p38 while maintaining selectivity against other kinases, thereby expanding the therapeutic window without sacrificing specificity

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11866764B2Method for testing and screening p38 MAP kinase modifiers

Publication Date: 2024.01.09 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

This invention provides compounds that inhibit p38 mitogen-activated protein kinase. Moreover, the invention provides methods for testing a candidate compound for a p38 mitogen-activated protein kinase modifying activity by calculating the level of relocalization of an SMN complex component from the cytoplasm to the nucleus of a cell. Additionally, the invention provides a kit and a system for calculating the same.