SRC Inhibitor Hybrids Targeting Disordered Regions for Selectivity
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Solution Overview
Problem
Current Src inhibitors approved by FDA are ineffective for solid tumors due to off-target effects and toxic side effects, limiting their dosage, and they fail to selectively inhibit Src in cancer cells.
Innovation Solution
Development of compounds with a hydrophobic, rigid non-peptidic framework linked to peptides based on the Src sequence, specifically targeting the intrinsically disordered regions using click chemistry to inhibit Src activity in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FDA-approved Src inhibitors are used to treat solid tumors, then Src kinase activity is inhibited, but off-target effects and toxic side effects occur that limit dosage and effectiveness
Solution Approach 1:
The invention segments the Src protein into two distinct targets: the kinase domain and the intrinsically disordered N-terminal region (residues 1-86). By designing compounds that specifically target the disordered region rather than the kinase domain, the patent achieves Src inhibition without affecting other kinases that share similar kinase domains, thereby eliminating off-target effects while maintaining therapeutic effectiveness
Solution Approach 2:
The patent applies local quality by creating compounds with specific structural features that match the unique properties of the intrinsically disordered region of Src. The compounds contain hydrophobic moieties and specific amino acid sequences (such as SH4 and Unique domain motifs) that selectively bind to the disordered region's transient structures, providing high selectivity for Src over other kinases and reducing toxic side effects
2Reliability
If peptide-based inhibitors are used to target intrinsically disordered regions, then selectivity for Src in cancer cells is achieved, but peptide degradation by proteases limits stability and efficacy
Solution Approach 1:
The invention creates composite molecules that combine peptide sequences derived from the intrinsically disordered region of Src with non-peptide hydrophobic backbones. This hybrid structure retains the sequence-specific selectivity of peptides for binding to Src's disordered region while the non-peptide backbone provides resistance to protease degradation, thereby achieving both selectivity and stability
Solution Approach 2:
The non-peptide hydrophobic backbone acts as an intermediary that mediates between the peptide sequence and the protein target. It provides a stable structural framework that protects the peptide sequence from enzymatic degradation while maintaining the binding affinity and selectivity for the intrinsically disordered region of Src through specific interactions
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 compounds effectively inhibit the proliferation and migration of Src-expressing cancer cells without toxicity, demonstrating potential as anticancer drugs.
Implementation Method 1
The use of the click reaction Cu(I)catalyzed azide-alkyne cycloaddition (CuAAC) facilitates the access to these hybrid compounds
Data Source
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AI summary
The present invention relates to the chemical and medical field, in particular to the synthesis of new molecules by click chemistry with anticancer properties. More specifically, the present invention relates to new compounds, pharmaceutical compositions comprising said compounds and their use in therapy, such as in cancer therapy.