Aminopyrimidine Inhibitor Selectivity for Drug-Resistant EGFR Mutations

Solution Overview

Problem

Current EGFR inhibitors, such as gefitinib and erlotinib, face challenges with acquired resistance due to the T790M mutation, leading to severe toxic side effects and reduced efficacy in non-small cell lung cancer treatment, necessitating the development of more selective inhibitors that target mutant EGFR without affecting wild-type EGFR.

Innovation Solution

A novel aminopyrimidine compound with improved EGFR kinase inhibitory activity and high selectivity for T790M and L858R mutations, designed to treat and prevent EGFR kinase-mediated diseases, is developed, which can be administered in pharmaceutical compositions with excipients for various treatment routes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If inhibitors targeting T790M mutation (such as BIBW2992, AZD9291, CO-1686) are used, then efficacy against drug-resistant EGFR is improved, but selectivity against wild-type EGFR is reduced leading to severe toxic side effects

Engineering Contradiction:

Improveefficacy against T790M mutationVSAvoidtoxic side effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by designing the aminopyrimidine compound with specific structural features (substituents at positions 5, 6, and 7 of the pyrimidine ring) that create localized interactions with the T790M mutation site. This enables the inhibitor to selectively bind to the mutant EGFR at the methionine residue while avoiding the wild-type EGFR, thereby achieving high selectivity and reducing toxic side effects on normal tissues

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the chemical structure parameters of EGFR inhibitors, specifically introducing amino pyrimidine core structures with varying substituents (R1, R2, R3, R4, R5 groups) to optimize the binding affinity and selectivity profile. These structural parameter adjustments enable the compound to distinguish between T790M mutant and wild-type EGFR based on subtle conformational differences

Inventive Principle:

Principle #35Parameter changes

2Reliability

If third-generation EGFR inhibitors (AZD9291, CO-1686) are used, then inhibition of T790M-resistant mutations is improved, but inhibitory effect on wild-type EGFR increases causing toxicity

Engineering Contradiction:

Improveinhibition of T790M-resistant mutationsVSAvoidtoxicity from wild-type EGFR inhibition

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by designing the aminopyrimidine compound with specific structural features (substituents at positions 5, 6, and 7 of the pyrimidine ring) that create localized interactions with the T790M mutation site. This enables the inhibitor to selectively bind to the mutant EGFR at the methionine residue while avoiding the wild-type EGFR, thereby achieving high selectivity and reducing toxic side effects on normal tissues

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent applies inversion by reversing the conventional approach: instead of designing inhibitors that broadly inhibit EGFR and hoping for selectivity, the aminopyrimidine compound is designed to specifically target the T790M mutation through unique structural features that exploit the mutation's altered binding pocket, thereby inverting the selectivity paradigm

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If gefitinib and erlotinib are used, then therapeutic effect on non-small cell lung cancer is improved, but acquired resistance due to T790M mutation develops reducing long-term efficacy

Engineering Contradiction:

Improvetherapeutic effectVSAvoidlong-term efficacy

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent applies preliminary action by designing the aminopyrimidine compound with pre-optimized structural features that anticipate and counteract the T790M resistance mechanism. The compound's molecular structure is预先 designed to fit the T790M mutant binding pocket, enabling it to effectively inhibit EGFR even in the presence of the T790M mutation and prevent resistance development

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent employs parameter changes by modifying the chemical structure parameters of EGFR inhibitors, specifically introducing amino pyrimidine core structures with varying substituents (R1, R2, R3, R4, R5 groups) to optimize the binding affinity and selectivity profile. These structural parameter adjustments enable the compound to distinguish between T790M mutant and wild-type EGFR based on subtle conformational differences

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3492462B1Amino pyrimidine compound for inhibiting protein tyrosine kinase activity

Publication Date: 2023.08.30 SHENZHEN TARGETRX INC

AI summary

An amino pyrimidine compound for inhibiting protein tyrosine kinase activity, a pharmaceutical composition thereof, preparation therefor, and an application hereof. Specifically, an amino pyrimidine compound represented by formula (I), R1, R2, L, Y, R6, W, A, m, and n being defined in the specification, and a pharmaceutically acceptable salt, a stereoisomer, a solvent compound, a hydrate, a polymorphism, a prodrug, or an isotope variant thereof. The compound can be used for treating and/or preventing protein tyrosine kinase-related diseases such as cell proliferative diseases, cancers, and immune diseases.