Cell-Penetrating Peptides for MYB:CBP Disruption in AML
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Solution Overview
Problem
Current therapies for pediatric and adult acute myeloid leukemia (AML) have not seen significant improvements over the last 30 years, particularly for high-risk molecular features and chemoresistant cases, due to the pharmacologic challenges of targeting transcription factors and protein-protein interactions, such as the MYB:CBP complex.
Innovation Solution
Development of single-chain peptides comprising a cell penetrating peptide sequence from HIV-TAT and a CBP binding peptide sequence from MYB, either in L-amino acids or retro-inverso D-amino acids, to interfere with the MYB:CBP complex, disrupting downstream gene regulation and leukemogenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy is used to treat AML, then some leukemic cells are killed, but therapeutic efficacy is limited particularly for high-risk molecular features and chemoresistant cases
Solution Approach 1:
The patent extracts and targets the specific molecular mechanism (MYB:CBP complex) that drives leukemogenesis in AML. By identifying and isolating this critical protein-protein interaction, the invention enables selective disruption of the oncogenic pathway without affecting normal cellular functions, thereby overcoming chemoresistance while maintaining therapeutic efficacy.
Solution Approach 2:
The patent introduces small molecule inhibitors as intermediary compounds that mediate the disruption of the MYB:CBP interaction. These inhibitors act as molecular mediators that bind to one component of the complex (either MYB or CBP) and prevent their interaction, thereby blocking downstream leukemogenic signaling without requiring direct targeting of the transcription factor DNA-binding domain.
2Reliability
If transcription factors and protein-protein interactions are targeted, then specific molecular mechanisms can be disrupted, but pharmacologic challenges hinder effective therapy development
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure, concentration, and binding affinity of the inhibitor molecules to optimize their ability to disrupt the MYB:CBP interaction. By systematically varying these parameters, the invention overcomes the pharmacologic challenges of targeting protein-protein interactions while maintaining specificity and effectiveness.
3Reliability
If the MYB:CBP complex is targeted to block leukemogenic activity, then downstream gene regulation is disrupted, but the necessary intranuclear physical interactions provide a challenging target for drug development
Solution Approach 1:
The patent uses small molecule inhibitors as intermediaries that can access the nuclear environment and mediate disruption of the MYB:CBP interaction. These inhibitors serve as soluble mediators that can diffuse into the nucleus and bind to their targets, overcoming the accessibility challenges of targeting intranuclear protein-protein interactions.
Data Source
AI summary
Single chain peptides comprising either a cell penetrating HIV-TAT peptide sequence and a MYB:CBP complex interfering peptide sequence from MYB, or comprising a cell penetrating HIV-TAT peptide sequence, a CBP binding peptide sequence from CREB and a MYB:CBP complex interfering peptide sequence from MYB, are provided for use in preventing MYB:CBP complex formation and downstream events leading to cancer, in particular a leukemia. Both L-amino acid single chain peptides and retro-inverso single chain peptides are provided.