SHP2 N-SH2 Domain Peptide Inhibitors for Cancer
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies for cancer and RASopathies, particularly those targeting SHP2, face challenges due to lack of target specificity and off-target effects, with existing inhibitors being ineffective against activating PTPN11 mutants and having poor bioavailability.
Innovation Solution
Development of peptide-based molecules with low nM affinity to the N-SH2 domain of SHP2, designed to inhibit SHP2 protein-protein interactions, which are resistant to degradation and facilitate cell uptake, thereby targeting the SHP2 protein-protein interactions for therapeutic intervention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing SHP2 inhibitors are used, then SHP2 activity is inhibited, but target specificity is poor and off-target effects occur
Solution Approach 1:
The patent applies local quality by designing peptides that specifically target the N-SH2 domain of SHP2 with high affinity and selectivity. The peptide sequence is optimized to interact exclusively with the N-SH2 domain, thereby achieving localized inhibition at the critical binding interface without affecting other SHP2 domains or off-target proteins, thus resolving the specificity issue.
Solution Approach 2:
The patent segments the SHP2 protein into functional domains (N-SH2, C-SH2, catalytic domain) and targets specifically the N-SH2 domain with the peptide inhibitor. This segmentation approach allows selective inhibition of the critical binding interface while leaving other domains intact, improving target specificity and reducing off-target effects.
2Reliability
If existing SHP2 inhibitors are used, then SHP2 activity is inhibited, but effectiveness against activating PTPN11 mutants is poor
Solution Approach 1:
The patent applies parameter changes by modifying the peptide sequence and structural parameters to optimize binding affinity and specificity for the N-SH2 domain. The peptide is designed with specific amino acid residues that maintain high affinity binding even in the presence of activating PTPN11 mutations, thereby preserving effectiveness against mutant forms while maintaining selectivity.
3Reliability
If existing SHP2 inhibitors are used, then SHP2 activity is inhibited, but bioavailability is poor
Solution Approach 1:
The patent employs composite material strategies by combining peptide-based inhibitors with cell-penetrating peptide (CPP) sequences. This composite approach creates a conjugate that not only inhibits SHP2 but also facilitates cellular uptake and stability, thereby improving bioavailability while maintaining peptide integrity through the protective effect of the CPP structure.
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 peptides effectively inhibit SHP2 protein-protein interactions, offering a new therapeutic strategy for cancer and RASopathies by selectively targeting the N-SH2 domain, potentially overcoming the limitations of existing inhibitors and providing a tool for investigating SHP2 function.
Implementation Method 1
peptide-based molecules with low nM affinity to the N-SH2 domain of SHP2, designed to inhibit SHP2 protein-protein interactions
Data Source
AI summary
The present invention relates to a peptide having the sequence from N-terminus to C-terminus X-2X-1ZX1X2X3X4X5 whereinZ is tyrosine, phosphotyrosine or a non-natural analogue of phosphotyrosine, such as phosphonodifluoromethyl phenylalanine (F2Pmp)X-2 is a hydrophobic amino acid, such as Leu, Ile, Val, Phe, Tyr, Trp and MetX-1 is any amino acidX1 is a hydrophobic amino acid, such as Ile, Leu, Val, Phe, Tyr, Trp and MetX3 is a hydrophobic amino acid, such as Leu, Ile, Val, Phe, Tyr, Trp and MetX5 is a hydrophobic amino acid, such as Trp, Ile, Val, Phe, Tyr, and MetX2 and X4 are anionic amino acids, preferably each independently is Asp or Glu. The peptide inhibits protein-protein interactions of the Src homology 2 domain-containing phosphatase 2 (SHP2), for the treatment of cancer and RASopathies and as a biomedical research tool.