Pyridopyrimidinone Kinase Inhibitors for RIPK2 and ALK2 Selectivity
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Solution Overview
Problem
Current treatments for diseases associated with aberrant protein kinase activity, such as inflammatory bowel disease, multiple sclerosis, bone diseases, cardiovascular diseases, and certain cancers, lack effective inhibitors targeting receptor interacting kinase 2 (RIPK2) and Activin-like kinase 2 (ALK2), which are implicated in these conditions and can exacerbate inflammation.
Innovation Solution
Development of pyrido[2,3-d]pyrimidin-7-ones and related compounds that act as dual inhibitors of RIPK2 and ALK2, or preferentially inhibit these kinases, providing therapeutic benefits through pharmaceutical compositions for oral, injectable, or inhalable administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for autoimmune and inflammatory diseases, then existing therapeutic options are available, but effective inhibition of RIPK2 and ALK2 is lacking
Solution Approach 1:
The patent applies parameter changes by systematically varying chemical parameters of the pyrido[2,3-d]pyrimidin-7-one core structure, including substitutions at positions 2, 6, and 8 with different functional groups (halogens, alkyl groups, aryl groups, heteroaryl groups). This allows optimization of binding affinity to RIPK2 and ALK2 kinases while maintaining selective inhibition, thereby improving therapeutic efficacy and target specificity simultaneously
Solution Approach 2:
The patent employs composite materials by creating hybrid molecular structures that combine the pyrido[2,3-d]pyrimidin-7-one core with various substituent groups. These composite structures (e.g., compounds with both hydrophobic and hydrophilic regions, or with specific H-bonding capabilities) enable simultaneous optimization of kinase binding affinity and selectivity, resolving the contradiction between therapeutic efficacy and target specificity
2Reliability
If pyrido[2,3-d]pyrimidin-7-ones are developed to inhibit RIPK2 and ALK2, then therapeutic benefits are achieved, but the compounds must selectively distinguish between multiple kinase targets
Solution Approach 1:
The patent applies segmentation by dividing the kinase binding interface into distinct regions that correspond to specific structural elements of the pyrido[2,3-d]pyrimidin-7-one molecule. The core structure interacts with the ATP-binding pocket, while specific substituents (e.g., at position 6 or 8) are designed to interact with disease-specific kinase residues. This segmentation allows selective inhibition of RIPK2 and ALK2 while simplifying the overall molecular design strategy
Solution Approach 2:
The patent employs universality by designing a core pyrido[2,3-d]pyrimidin-7-one structure that can serve multiple functions: ATP-competitive binding, selective kinase targeting, and potential for prodrug conversion. The core scaffold maintains consistent binding to the ATP pocket across different kinase targets, while variable substituents provide target-specific interactions, reducing molecular complexity while maintaining inhibitory activity
Data Source
AI summary
Identified compounds demonstrate protein kinase inhibitory activity. More specifically, the compounds are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit.