Pyrimidine-2,4-diamine derivatives overcome EGFR T790M and C797S resistance

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current EGFR tyrosine kinase inhibitors (TKIs) face rapid resistance development, particularly due to the T790M mutation, and existing drugs like AZD9291 lose efficacy over time due to triple mutations such as C797S.

Innovation Solution

A pyrimidine-2,4-diamine derivative with a specific chemical structure, represented by Formula 1, is developed. This compound exhibits high inhibitory activity against EGFR and HER2 mutations, including triple mutations like EGFR del19/T790M/C797S, and is designed for use in cancer treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional EGFR TKIs (gefitinib, erlotinib) are used, then initial cancer treatment effectiveness is improved, but resistance develops rapidly due to T790M mutation

Engineering Contradiction:

Improveinitial treatment effectivenessVSAvoidduration of treatment efficacy

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the chemical structure of EGFR TKIs by changing molecular parameters (introducing specific substituents at defined positions) to create third-generation inhibitors that overcome resistance mutations while maintaining effectiveness against wild-type EGFR

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite inhibitor structures combining multiple functional groups (pyrimidine-2,4-diamine core with specific side chains) to achieve dual activity against both sensitizing mutations and resistant mutations simultaneously

Inventive Principle:

Principle #40Composite materials

2Reliability

If AZD9291 is used to overcome T790M resistance, then efficacy against resistant mutations is improved, but triple mutations (C797S) render the drug ineffective over time

Engineering Contradiction:

Improveefficacy against resistant mutationsVSAvoidduration of treatment efficacy

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent further modifies the chemical structure by introducing specific substituents (e.g., at positions R1-R8 in Formula 1) to create fourth-generation inhibitors that overcome triple mutations including C797S while maintaining activity against prior resistance mutations

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention designs inhibitors with pre-configured molecular structures that anticipate and prevent the development of resistance mutations before they can render the treatment ineffective

Inventive Principle:

Principle #10Preliminary action

3Reliability

If irreversible mutation-selective inhibitors are used, then activity against T790M mutation is improved, but covalent bond mutation (C797S) neutralizes the effect

Engineering Contradiction:

Improveactivity against T790M mutationVSAvoidneutralization by C797S mutation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the binding mechanism parameters by introducing reversible binding interactions and alternative binding sites that remain functional even when the primary covalent binding site is mutated at C797

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250171416A2Novel pyrimidine-2,4-diamine derivatives, preparation method therefor, and pharmaceutical composition containing same as active ingredient for prevention or treatment of cancer

Publication Date: 2025.05.29 KOREA RES INST OF CHEM TECH

AI summary

The present invention relates to a pyrimidine-2,4-diamine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer, comprising the same as an active ingredient. The pyrimidine-2,4-diamine derivative exhibits a high inhibitory ability against EGFR and HER2 mutations, and thus can be advantageously used in the treatment of cancer in which EGFR and HER2 mutations have occurred. In addition, the pyrimidine-2,4-diamine derivative exhibits a significant synergistic effect when administered in combination, and thus may be advantageously used in combination therapy.