Thienopyrimidine Compounds Inhibit Menin-MLL Interaction
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Solution Overview
Problem
Current therapeutic strategies are inadequate for treating leukemias associated with chromosomal translocations affecting the MLL gene, particularly in infants, where the interaction between menin and MLL fusion proteins drives leukemogenesis, leading to poor prognosis.
Innovation Solution
Development of thienopyrimidine and thienopyridine class compounds that inhibit the binding of MLL fusion proteins to menin, disrupting the oncogenic interaction and potentially offering a novel therapeutic approach for leukemias.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic strategies are used, then treatment of MLL-associated leukemias is attempted, but treatment effectiveness is insufficient due to poor prognosis and inadequate existing approaches
Solution Approach 1:
The patent applies parameter changes by developing novel small molecule compounds with specific chemical structures (thienopyrimidine and thienopyridine cores) that fundamentally change the therapeutic parameter of drug-mmenin interaction. These compounds possess unique structural parameters (substituents at positions 2, 4, 5, 6, and 7 of the core rings) that enable them to bind to the menin protein and inhibit its interaction with MLL fusion proteins, thereby improving treatment effectiveness where previous therapies failed
Solution Approach 2:
The patent employs an intermediary approach by introducing small molecule compounds as mediators that interfere with the protein-protein interaction between menin and MLL fusion proteins. These intermediary compounds bind to the menin protein and prevent the formation of the oncogenic complex, effectively blocking the leukemogenic pathway without directly targeting the MLL fusion protein itself
2Reliability
If novel therapeutic compounds are developed to target menin-MLL interaction, then treatment effectiveness may improve, but drug development complexity and time increase
Solution Approach 1:
The patent applies segmentation by dividing the menin protein binding interface into discrete interaction regions that can be targeted by specific chemical groups on the small molecule compounds. The compounds are designed with segmented functional groups (electron-withdrawing groups at position 2, substituents at positions 4, 5, 6, and 7) that independently contribute to binding affinity and selectivity, allowing systematic optimization of drug candidates
Solution Approach 2:
The patent systematically varies chemical parameters of the core structures and substituents to optimize drug properties. By changing parameters such as the type of electron-withdrawing group, the nature and position of substituents on the thienopyrimidine or thienopyridine core, and the linkers connecting aromatic rings, the invention creates a library of compounds with tuned binding affinities and pharmacological properties, streamlining the development process
Data Source
AI summary
The present disclosure relates generally to thienopyrimidine and thienopyridine compounds and methods of use thereof. In particular embodiments, the present disclosure provides compositions comprising thienopyrimidine and thienopyridine compounds of Formula 3:and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins.