[1,3]Diazino[5,4-d]Pyrimidines for HER2 Exon 20 Mutants
Solution Overview
Problem
Current HER2 exon 20 mutant inhibitors are ineffective due to EGFR wild type-mediated dose-limiting toxicity, and there is a need for compounds that selectively target HER2 exon 20 mutant proteins while sparing EGFR wild type.
Innovation Solution
Development of [1,3]diazino[5,4-d]pyrimidines that bind orthosterically and covalently to the tyrosine kinase domain of wild type and mutant HER2 exon 20, acting as selective inhibitors while sparing EGFR wild type.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pan-ERBB inhibitors like afatinib are used to target HER2 exon 20 mutations, then HER2 mutant signaling is inhibited, but EGFR wild type-mediated dose-limiting toxicity occurs
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular features ( Formula I structure with specific R1-R6 substituents) that create selective binding characteristics. The compounds exhibit different binding affinities and mechanisms for HER2 exon 20 mutants versus EGFR wild type, allowing targeted inhibition of the mutant form while sparing the wild type form from toxic effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters (substituents at positions R1-R6, heterocyclic configurations, stereochemistry) to optimize the balance between HER2 exon 20 mutant inhibition potency and EGFR wild type selectivity. This structural parameter optimization enables the compounds to achieve high efficacy against mutants while maintaining safety profile.
2Reliability
If existing HER2 inhibitors are used, then HER2 signaling is inhibited, but selectivity over EGFR wild type is insufficient
Solution Approach 1:
The patent applies segmentation by dividing the ERBB family inhibition into separate selective mechanisms: compounds that specifically target HER2 exon 20 mutants through covalent binding to the mutant kinase domain, versus EGFR wild type inhibition. This segmentation allows independent optimization of each target's binding characteristics without compromising the other.
Solution Approach 2:
The patent uses an intermediary approach by introducing specific molecular intermediaries (the Formula I compounds with particular R1-R6 groups) that mediate selective binding to HER2 exon 20 mutants. These intermediaries act as selective bridges that connect the inhibitor to the mutant form while avoiding direct interaction with EGFR wild type, thus achieving high selectivity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds demonstrate improved selectivity and efficacy over EGFR wild type, with enhanced pharmacokinetic and pharmacological profiles, including good metabolic stability.
Implementation Method 1
bind orthosterically and covalently to the tyrosine kinase domain of wild type and mutant HER2 exon 20
Implementation Method 2
bind orthosterically and covalently to the tyrosine kinase domain of wild type and mutant HER2 exon 20
Data Source
AI summary
The present invention relates to new [1,3]diazino[5,4-d]pyrimidines and derivatives of Formula (I), wherein the groups R1, R2, R3 and R4 have the meanings given in the claims and specification, their use as inhibitors of HER2 and its mutants, pharmaceutical compositions which contain such compounds and their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases.