Aurora A Inhibitors That Destabilize MYCN in Cancer Cells
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Solution Overview
Problem
Current chemical techniques have proven challenging for direct and efficient pharmacologic targeting of MYC transcription factors, which are difficult to bind due to their alpha helical structure, and MYC proteins contribute to a wide range of human tumors through overexpression, amplification, or stabilizing point mutations.
Innovation Solution
Development of a class of Aurora Kinase A inhibitors, such as CD532, that disrupt the native conformation of Aurora A, leading to the degradation of MYCN protein in MYCN-expressing neuroblastoma cell lines by destabilizing interactions between Aurora A and MYCN.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If direct pharmacologic targeting of MYC transcription factors is attempted using current chemical techniques, then MYC-specific inhibition may be achieved, but the challenge of MYC's alpha helical structure with no apparent binding surfaces makes this approach difficult and inefficient
Solution Approach 1:
The patent uses Aurora Kinase A as an intermediary target instead of directly targeting MYC. By inhibiting Aurora A, which phosphorylates and stabilizes MYC, the patent achieves indirect MYC inhibition. This mediator approach bypasses the problem of MYC's lack of direct binding surfaces while still achieving therapeutic effect against MYC-driven cancers.
Solution Approach 2:
The patent changes the target parameter from MYC itself to Aurora Kinase A, which has druggable ATP-binding sites. This parameter change allows small molecule inhibitors to effectively bind and inhibit the kinase, thereby indirectly controlling MYC stability and expression levels without requiring direct MYC binding.
2Adaptability or versatility
If MYC proteins are targeted directly, then MYC-specific gene regulation may be modulated, but the extended alpha helices structure provides no apparent surfaces for small molecule binding
Solution Approach 1:
Aurora Kinase A serves as a mediator that controls MYC stability through phosphorylation. By targeting Aurora A's kinase activity with small molecules, the patent achieves modulation of MYC levels and gene expression without requiring direct interaction with MYC's inaccessible alpha helical structure.
Solution Approach 2:
The patent replaces the mechanical challenge of fitting small molecules into MYC's alpha helical structure with a biochemical approach targeting Aurora A's active site. This substitution uses the kinase's enzymatic mechanism (ATP binding and phosphate transfer) as a more accessible target for pharmacologic intervention.
3Ease of manufacture
If Aurora Kinase A inhibitors are used to indirectly target MYC, then the drug development process becomes more feasible, but the indirect mechanism may affect off-target genes regulated by MYC pathways
Solution Approach 1:
The patent changes the target from MYC to Aurora A, accepting that this will indirectly affect all MYC-regulated genes. The benefit of druggability and feasibility outweighs the potential off-target effects, as selective Aurora A inhibition can still achieve therapeutic benefit in MYC-driven cancers while minimizing effects on non-MYC pathways.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The inhibitors effectively inhibit Aurora Kinase A, causing a dramatic shift in its structure and resulting in the rapid loss of MYCN protein, offering a therapeutic approach for MYCN-driven cancers.
Implementation Method 1
Aurora Kinase inhibitors and methods of use
Implementation Method 2
These kinases direct sequential phosphorylation and dephosphorylation of conserved residues in MYC proteins, which target them for ubiquitination and degradation by the proteasome
Data Source
AI summary
Disclosed herein inter alia are compositions and methods useful in the treatment of cancer and for modulating the activity of Aurora A kinase and/or a Myc family protein.