Allosteric Monobody Modulating Aurora A Kinase Specificity
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Solution Overview
Problem
Current small molecule kinase inhibitors targeting the ATP binding site of Aurora A kinase are not specific, leading to side effects due to non-specific binding to other kinases, necessitating the development of methods to specifically modulate Aurora A kinase activity.
Innovation Solution
Development of antibody mimetics, such as monobodies, that specifically bind to the allosteric PIF pocket of Aurora A kinase, disrupting TPX2 binding and altering kinase activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule kinase inhibitors are developed to target the ATP binding site of Aurora A kinase, then kinase activity can be modulated, but specificity is reduced leading to side effects from non-specific binding to other kinases
Solution Approach 1:
The invention extracts the binding function from the conventional ATP-binding site targeting approach and relocates it to a unique allosteric PIF pocket site on Aurora A kinase. This extraction of the binding target from the conserved ATP site to the unique PIF pocket enables specific modulation of Aurora A kinase activity without affecting other kinases that share the same ATP binding site architecture.
Solution Approach 2:
The invention applies local quality by targeting a specific unique region (the PIF pocket) of the Aurora A kinase structure rather than the conserved ATP binding site. The PIF pocket contains unique amino acid residues that are not present in other kinases, allowing the antibody mimetic to bind with high specificity to Aurora A while leaving other kinases unaffected, thus eliminating side effects.
2Object-affected harmful factors
If antibody mimetics are designed to bind to the allosteric PIF pocket of Aurora A kinase, then specificity is improved, but the complexity of the therapeutic composition increases
Solution Approach 1:
The invention uses antibody mimetics that copy the binding capability of full-sized antibodies but with reduced complexity. These mimetics are smaller, simpler molecules that retain the specific binding function to the PIF pocket while eliminating the complex quaternary structure and multiple domains of conventional antibodies, thus reducing compositional complexity while maintaining high specificity.
Solution Approach 2:
The invention segments the therapeutic approach by using smaller antibody mimetic molecules rather than full-sized antibodies. This segmentation reduces the molecular complexity and size of the therapeutic composition while preserving the critical binding function to the PIF pocket, making the composition simpler yet equally specific.
Data Source
AI summary
The present invention features an antibody mimetic, or an antigen binding fragment thereof, that specifically binds to an allosteric site of Aurora A kinase, therapeutic compositions comprising this antibody mimetic, and the use of the monobody to modulate Aurora A kinase for the treatment of cancer.