Macrocyclic Indolin-2-one Kinase Inhibitors for Multi-Target Anti-Tumor Therapy
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Solution Overview
Problem
Current cancer therapies lack effective targets for inhibiting aberrant cellular proliferation and mitotic defects that lead to aneuploid cell formation, particularly in tumors where Aurora and CDK kinases are upregulated, and there is a need for compounds with broad pharmacological activity beyond single biological processes.
Innovation Solution
Development of macrocyclic indolin-2-ones and aza-indolin-2-ones that inhibit protein kinases involved in cellular mitosis, including Aurora and CDK kinases, offering anti-tumor activity and additional GSK-3 inhibitory effects for treating various diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current cancer therapies target single biological processes, then they achieve specific anti-tumor effects, but they lack broad pharmacological activity and effective targets for inhibiting aberrant cellular proliferation
Solution Approach 1:
The patent applies universality by designing indolin-2-one and aza-indolin-2-one compounds that can inhibit multiple kinase families simultaneously. The compounds are engineered to target Aurora kinases (A and B), CDKs (1, 2, 5, 7, 9), and GSK-3, allowing a single agent to address aberrant cellular proliferation through multiple mechanisms rather than relying on a single biological process
2Adaptability or versatility
If therapies focus on multiple kinase targets, then broad anti-tumor activity is achieved, but the complexity of the treatment regimen increases
Solution Approach 1:
The patent merges multiple kinase inhibition capabilities into a single compound molecule. The indolin-2-one and aza-indolin-2-one structures are designed to simultaneously bind and inhibit Aurora kinases, CDKs, and GSK-3, consolidating what would otherwise require multiple separate drugs into one unified treatment agent
3Ease of operation
If single-kinase inhibitors are used, then the mechanism of action is simple and well-defined, but they lack the ability to address multiple pathways involved in mitotic defects and aneuploid cell formation
Solution Approach 1:
The compounds are designed with universal kinase inhibition capability, allowing them to interfere with multiple pathways involved in mitotic defects simultaneously. By targeting Aurora kinases (centrosome separation, spindle formation), CDKs (cell cycle progression), and GSK-3 (cellular proliferation), the compounds address mitotic defects through multiple coordinated mechanisms while maintaining a unified mode of action
Data Source
AI summary
The present invention relates to compounds or pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to certain indolin-2-ones and aza-indolin-2-ones which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body, in particular such compounds are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumor growth, rheumatoid arthritis, restenosis and atherosclerosis. Formula (I) a N-oxide form, a quaternary anime or a stereochemically isomeric form thereof, wherein Z represents N or CH.