KIT and PDGF-R Inhibitor Compounds Overcoming D842V Resistance

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Solution Overview

Problem

Current therapeutic agents are inadequate in effectively inhibiting mutant KIT and PDGF-R, particularly in cases of KIT mutations leading to disorders like systemic mastocytosis, GIST, and resistance to existing tyrosine kinase inhibitors such as the D842V mutation in PDGFRα.

Innovation Solution

Development of compounds with a specific structural formula that modulate the activity of Kit and target mutant KIT and PDGF-R, including a pharmaceutically acceptable salt, to inhibit aberrant cell proliferation and genomic instability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing tyrosine kinase inhibitors are used, then KIT inhibition is achieved, but resistance develops (particularly D842V mutation in PDGFRα)

Engineering Contradiction:

ImproveKIT inhibition efficacyVSAvoidResistance to inhibitors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs parameter changes by developing compounds with modified chemical structures (Formula I with various substituents W, Ring A, X, Y, Z, L, RA, RB, RC, R1, R2, m, p, q) that alter the binding characteristics to KIT and PDGFRα, thereby overcoming resistance mechanisms that developed against previous inhibitors

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite therapeutic agents that target multiple receptors (KIT and PDGFRα) simultaneously through a single compound structure, providing broad-spectrum inhibition that addresses resistance to single-target inhibitors

Inventive Principle:

Principle #40Composite materials

2Reliability

If KIT mutations occur (exon 11, 7, 8, 9, 13, 14, 17, 18), then constitutive activation leads to high cell division rate, but existing agents fail to effectively inhibit mutant KIT

Engineering Contradiction:

ImproveMutant KIT inhibitionVSAvoidConstitutive activation and genomic instability

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (various W groups, Ring A options, and substituent patterns) that are optimized to bind to and inhibit mutant KIT variants with constitutive activation, addressing the localized problem of mutation-specific resistance

Inventive Principle:

Principle #3Local quality

3Productivity

If therapeutic agents are designed to inhibit KIT, then cell proliferation is controlled, but selectivity and efficacy against specific mutations remain insufficient

Engineering Contradiction:

ImproveCell proliferation controlVSAvoidMutation-specific inhibition precision

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The patent employs segmentation by dividing the inhibitory function across multiple compound variants (Formula I with different W, Ring A, X, Y, Z, L, RA, RB, RC, R1, R2, m, p, q combinations), where each variant can be optimized for specific mutation types while maintaining overall KIT inhibition capability

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS9884861B2Compositions useful for treating disorders related to kit

Publication Date: 2018.02.06 BLUEPRINT MEDICINES CORP

AI summary

Compounds and compositions useful for treating disorders related to KIT and PDFGR are described herein.