Crystalline Menin Inhibitor Forms for MLL-Driven Leukemia
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for leukemias, such as acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL), are limited by the lack of effective targets for inhibiting the oncogenic activity of MLL fusion proteins, which are driven by the interaction between menin and the N-terminus of MLL fusion proteins, leading to uncontrolled cell proliferation and differentiation.
Innovation Solution
Development of crystalline forms of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile, which inhibit the interaction between menin and MLL proteins, thereby disrupting the oncogenic signaling pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for leukemias are used, then existing therapeutic options are maintained, but the effectiveness is limited due to lack of effective targets for inhibiting MLL fusion protein activity
Solution Approach 1:
The patent introduces menin as an intermediary target in the therapeutic approach. Instead of directly targeting the MLL fusion protein, the invention uses small molecule inhibitors that bind to menin, thereby indirectly inhibiting the menin-MLL interaction. This intermediary approach provides a viable therapeutic target that was previously unavailable, resolving the contradiction between maintaining therapeutic options and increasing treatment effectiveness.
2Object-generated harmful factors
If the menin-MLL interaction is inhibited, then oncogenic activity is reduced, but the complexity of identifying and targeting this interaction increases
Solution Approach 1:
The patent extracts the menin component from the menin-MLL interaction complex as a separate, druggable target. By focusing on menin rather than the entire interaction interface, the invention simplifies the target identification process while still achieving inhibition of oncogenic activity. The small molecule inhibitors are designed to bind specifically to menin, making the therapeutic approach more tractable despite the complexity of the original interaction.
3Reliability
If crystalline forms of the menin inhibitor are developed, then pharmaceutical stability and bioavailability are improved, but the manufacturing and characterization processes become more complex
Solution Approach 1:
The patent employs parameter changes in the crystallization process to obtain stable crystalline forms of the menin inhibitor. By adjusting parameters such as solvent composition, temperature, and pH, the invention achieves pharmaceutical-grade crystalline materials with improved stability and bioavailability. This systematic approach to parameter optimization balances the need for pharmaceutical quality with manufacturing feasibility.
Data Source
AI summary
Described herein are crystalline forms of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof.