Selective Purine SIK3 Inhibitors With Reduced PI3K Off-Targeting
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Solution Overview
Problem
There is an unmet need for new SIK3 inhibitors to treat diseases and disorders associated with SIK3-mediated events, particularly in conditions like cancer and autoimmune diseases, where existing treatments are inadequate.
Innovation Solution
Development of selective SIK3 inhibitors, such as (S)-3-(3-fluorophenyl)-2-(1-((8-hydroxy-9H-purin-6-yl)amino)propyl)-4H-chromen-4-one (Compound M1) and its pharmaceutically acceptable salts, which exhibit activity against SIK3 without affecting the δ and γ isoforms of PI3K, offering potential therapeutic benefits.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing SIK3 inhibitors are used, then SIK3 activity is inhibited, but selectivity against other kinase isoforms (particularly PI3K δ and γ) is compromised
Solution Approach 1:
The patent applies local quality by designing a compound with specific functional groups positioned to interact selectively with SIK3's unique binding pocket. The purine derivative structure features a substituted amino group at position 6 and a hydroxyl group at position 8, which are strategically positioned to form hydrogen bonds with residues unique to SIK3, thereby achieving high selectivity while maintaining potent inhibition.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of purine derivatives through systematic variation of substituents at different positions. By changing the nature and position of substituents (e.g., fluorine atoms, hydroxyl groups, amino groups), the patent optimizes both the potency and selectivity parameters of the inhibitors, achieving compounds that selectively target SIK3 while sparing PI3K isoforms.
2Adaptability or versatility
If broad-spectrum kinase inhibitors are used, then multiple kinase activities are inhibited, but therapeutic specificity for SIK3-mediated diseases is reduced
Solution Approach 1:
The patent applies the taking out principle by extracting the specific binding interactions that are unique to SIK3 from the general kinase inhibition mechanism. The compound design focuses on capturing the distinctive features of SIK3's ATP-binding pocket, particularly the interactions with residues that differ from PI3K isoforms, thereby isolating SIK3-specific inhibition while excluding off-target effects on other kinases.
Solution Approach 2:
The patent uses the intermediary principle by introducing specific functional groups in the purine derivative that act as mediators for selective binding to SIK3. These intermediary groups (such as the 6-amino and 8-hydroxyl substituents) facilitate specific hydrogen bonding interactions with SIK3 residues, serving as molecular mediators that distinguish SIK3 from other kinase isoforms and enable selective inhibition.
3Adaptability or versatility
If new SIK3 inhibitor compounds are developed, then therapeutic options for SIK3-mediated diseases are expanded, but complexity of drug development and validation increases
Solution Approach 1:
The patent applies universality by developing a series of purine derivative compounds that share a common core structure and mechanism of action against SIK3. This modular approach allows multiple compounds with varying substituents to target the same biological pathway (SIK3-mediated diseases), enabling broad therapeutic applications across different disease indications while using a standardized development platform that reduces overall complexity.
Data Source
AI summary
The present invention relates to novel inhibitors of salt-inducible kinase-3 (SIK3), methods of preparing them, pharmaceutical compositions containing them and methods for the treatment and/or prevention of kinase mediated diseases or disorders using them.