Lactam Arylfusedpyrimidine Inhibitors for Selective ErbB2 Targeting
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Solution Overview
Problem
Current treatments for cancers associated with ErbB2 overexpression, particularly those with tyrosine kinase inhibitors, face limitations due to inadequate selectivity for ErbB2 over EGFR, leading to toxicity concerns and reduced therapeutic efficacy, especially in cases with specific genetic alterations like EGFR exon 20 insertions and NRG1 gene fusions.
Innovation Solution
Development of novel compounds of specific formulas that selectively inhibit ErbB2 kinase activity, including mutant forms with Exon 20 mutations, to enhance therapeutic potency and safety by targeting ErbB2 over EGFR.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tyrosine kinase inhibitors are used to treat ErbB2-overexpressing cancers, then therapeutic benefit is achieved, but selectivity for ErbB2 over EGFR is insufficient leading to toxicity
Solution Approach 1:
The patent applies local quality by designing the inhibitor molecule with specific structural features ( Formula I with particular substituent patterns at positions R1, R2, R3, R4, R5, R6, R7, R8, R9, R10) that create localized interactions with the ErbB2 binding pocket. These localized structural modifications enhance selectivity for ErbB2 over EGFR by forming specific hydrogen bonds and hydrophobic interactions with unique residues in the ErbB2 kinase domain, thereby reducing off-target toxicity while maintaining therapeutic efficacy.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the inhibitor structure (different substituents, ring systems, and linkers in Formula I) to optimize the balance between ErbB2 potency and EGFR selectivity. By adjusting parameters such as the nature of substituents at R1-R10 positions and the core heterocyclic structure, the invention achieves enhanced therapeutic index through improved selectivity parameters.
2Reliability
If current TKIs are used at higher doses to overcome suboptimal target engagement, then therapeutic efficacy may improve, but toxicity increases
Solution Approach 1:
The patent addresses this contradiction by designing inhibitors with localized structural features that enhance binding affinity and selectivity for ErbB2. The specific substituent patterns in Formula I create optimized local interactions with the ErbB2 active site, ensuring robust target engagement at lower doses and thereby avoiding dose-dependent toxicities associated with current TKIs.
Solution Approach 2:
The invention applies parameter changes by optimizing key molecular parameters of the inhibitor (hydrophobicity, hydrogen bonding capacity, steric properties) to achieve high potency and selectivity. This allows effective target engagement at lower doses, improving the therapeutic window and reducing toxicity while maintaining or enhancing efficacy.
3Object-affected harmful factors
If TKIs are designed to be more selective for ErbB2, then toxicity is reduced, but efficacy against certain genetic alterations (EGFR exon 20 insertions, NRG1 fusions) may be compromised
Solution Approach 1:
The patent applies universality by designing the inhibitor in Formula I with a versatile molecular architecture that can accommodate multiple binding modes and interact with various ErbB2 conformations. The core heterocyclic structure combined with adjustable substituents (R1-R10) allows the molecule to effectively bind to ErbB2 regardless of specific genetic alterations (exon 20 insertions, point mutations, NRG1 fusions), while maintaining selectivity for ErbB2 over EGFR through conserved key interactions.
Solution Approach 2:
The invention employs dynamics by designing an inhibitor with flexible structural elements (variable linkers, rotatable bonds, and adaptable substituent positions in Formula I) that allow the molecule to adjust its conformation to fit different ErbB2 mutant structures. This dynamic adaptability enables the inhibitor to maintain high affinity and selectivity across diverse ErbB2 genetic alterations while preserving ErbB2-specific targeting.
Data Source
AI summary
The present disclosure relates generally to compounds and compositions thereof for inhibition of ErbB2, including mutant forms of ErbB2, particularly those harboring an Exon 20 mutation, methods of preparing said compounds and compositions, and their use in the treatment or prophylaxis of various cancers, such as lung, glioma, skin, head neck, salivary gland, breast, esophageal, liver, stomach (gastric), uterine, cervical, biliary tract, pancreatic, colorectal, renal, bladder or prostate cancer.