RET Kinase Inhibitors Selective Binding

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Solution Overview

Problem

Current RET inhibitors are limited in effectively targeting both wild-type RET and its resistant mutants, leading to treatment challenges due to toxicities from inhibiting other kinases and the development of resistance, which complicates cancer therapy, especially in cancers like papillary thyroid carcinoma and non-small cell lung cancer.

Innovation Solution

Development of specific compounds with structural Formula (I) and its pharmaceutically acceptable salts that selectively inhibit RET activity, including resistant mutants, by targeting the RET kinase domain, thereby reducing toxicities associated with other kinase inhibition and addressing resistance issues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If multi-kinase inhibitors are used to treat RET fusion-positive cancers, then RET activity is inhibited, but toxicities from inhibiting other kinases occur

Engineering Contradiction:

ImproveRET inhibition efficacyVSAvoidtoxicities from other kinase inhibition

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features (Formula I) that create selective binding characteristics. The compounds have a preferential binding mode that allows them to inhibit RET with higher affinity and selectivity compared to other kinases, thereby reducing off-target toxicities while maintaining RET inhibition efficacy.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent utilizes parameter changes by modifying the chemical structure of RET inhibitors to alter binding parameters. The compounds of Formula I have optimized pharmacological parameters that enable selective RET inhibition, achieving a favorable profile with reduced off-target kinase inhibition and associated toxicities.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If RET inhibitors are used to treat cancer, then RET activity is reduced, but resistance develops through kinase reactivation mutations

Engineering Contradiction:

ImproveRET inhibition efficacyVSAvoidresistance to therapy

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies universality by designing a broad-spectrum inhibitor that targets multiple RET variants. The compounds of Formula I are effective against wild-type RET as well as various resistant mutants (e.g., V804L, V804M, V804E, Y806C, Y806S, Y806H, G810R, G810S, L865V, L870F, S891A, M918T), providing universal inhibition across different RET configurations and preventing resistance development.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If higher doses of RET inhibitors are administered to overcome resistance, then RET inhibition improves, but toxicities increase

Engineering Contradiction:

ImproveRET inhibition efficacyVSAvoidtoxicities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by optimizing the pharmacological parameters of the compounds. The Formula I compounds have improved binding affinity and selectivity parameters that enable effective RET inhibition at lower doses, reducing the need for high-dose administration and associated toxicities while maintaining efficacy against resistant mutants.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS10183928B2Inhibitors of RET

Publication Date: 2019.01.22 BLUEPRINT MEDICINES CORP

AI summary

Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.