Small Molecule Inhibitors Targeting YEATS Domain Pi-Pi-Pi Stacking
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Solution Overview
Problem
Current therapies for mixed lineage leukemia (MLL) are inadequate, and there is a need for new targets for therapeutic intervention, particularly in addressing the aggressive nature of this disease which involves aberrant epigenetic landscapes and exploitation of chromatin machinery by cancer cells.
Innovation Solution
Development of small molecule inhibitors that target π-π-π stacking interactions in the YEATS protein domain, specifically designed to interfere with the interaction between the ENL YEATS domain and histone acetylation, thereby disrupting oncogenic gene expression programs in leukemic MLL-r cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for mixed lineage leukemia, then treatment is provided, but the therapies are inadequate and cannot effectively address the aggressive nature of the disease
Solution Approach 1:
The patent changes the therapeutic target from conventional approaches to specifically target the YEATS domain's π-π-π stacking interactions. By modifying the molecular interaction parameters at the protein-ligand interface, the invention achieves effective inhibition of MLL-r cell proliferation where previous therapies failed
Solution Approach 2:
The small molecule inhibitors act as intermediaries that disrupt the interaction between the YEATS domain and crotonylated histone H3. This intermediary approach allows the therapy to indirectly affect oncogenic gene expression programs by blocking the recognition and binding event
2Reliability
If small molecule inhibitors targeting π-π-π stacking interactions are developed, then selective killing of leukemic MLL-r cells is achieved, but the device complexity increases
Solution Approach 1:
The inhibitors are designed with specific local chemical features (conjugated/delocalized groups with aromatic rings) concentrated at the binding interface to disrupt π-π-π stacking. This localized functional design achieves high selectivity without requiring complex overall molecular structures
Solution Approach 2:
The inhibitor molecules are segmented into distinct functional components: a base oligomer (peptide backbone) and a side chain containing the conjugated/delocalized group. This segmentation allows independent optimization of each component's function while maintaining overall simplicity
3Reliability
If inhibitors are designed to interfere with ENL YEATS domain and histone acetylation interaction, then oncogenic gene expression programs are disrupted, but the manufacturing precision requirements increase
Solution Approach 1:
The patent employs standard peptide bond formations (amide linkages) and common amino acid residues, which can be manufactured using conventional peptide synthesis techniques. The structural parameters are chosen to match natural biochemical components, reducing manufacturing precision requirements while maintaining biological activity
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 achieve significant inhibitory activity at submicro/nanomolar levels, selectively targeting and killing leukemic MLL-r cells by disrupting the recruitment of RNA polymerase II to ENL-target genes, thus providing a potential therapeutic approach for acute leukemia.
Implementation Method 1
YEATS domains specifically recognize the lysine crotonylation marks on histones, accommodating the crotonyl group by forming π-π-π stacking using two conserved aromatic ring-containing amino acid residues
Data Source
AI summary
Disclosed herein are compositions and methods suitable for treating acute leukemia by inhibiting πππ stacking in the YEATS protein domain. YEATS protein domains are typically found in a variety of chromatin modification molecular complexes. Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Quantitative analysis of the inhibitory activity of YEATS domain inhibitors by use of a fluorescence-based assay revealed that several of the tested inhibitors achieved 50% inhibition at the submicro/nanomolar level. As such, provided is the use of small molecule inhibitors that target the ENL YEATS domain to selectively kill leukemic MLL-r cells.