Menin Inhibitor Crystalline Forms for Targeting MLL Fusion Leukemia
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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 impairment.
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 (Compound 1) or its solvates, which specifically inhibit the interaction between menin and MLL proteins, thereby disrupting the oncogenic pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for leukemias are used, then existing therapeutic approaches are maintained, but they are limited by the lack of effective targets for inhibiting the oncogenic activity of MLL fusion proteins
Solution Approach 1:
The patent extracts and isolates the menin-MLL interaction as a specific therapeutic target from the complex oncogenic pathway. By identifying menin as a discrete protein that binds to the N-terminus of MLL fusion proteins, the invention extracts this specific interaction point for targeted inhibition, converting the undifferentiated problem of 'lack of effective targets' into a specific actionable target.
Solution Approach 2:
The patent introduces small molecule compounds as intermediary substances that mediate between the therapeutic goal and the menin-MLL interaction. These compounds act as molecular mediators that bind to menin and prevent its interaction with MLL fusion proteins, thereby translating the abstract concept of 'target inhibition' into a concrete therapeutic mechanism.
2Reliability
If the menin-MLL interaction is inhibited, then oncogene expression is reduced and cell differentiation is promoted, but the development of effective inhibitors requires identification of specific molecular targets
Solution Approach 1:
The patent segments the oncogenic pathway into distinct functional components, specifically isolating the menin-MLL interaction as a separable target. By dividing the complex process of oncogene regulation into discrete molecular events (menin binding to MLL N-terminus), the invention makes the target detectable and measurable, overcoming the difficulty of identifying specific molecular targets within the broader oncogenic pathway.
Solution Approach 2:
The patent employs analytical techniques that detect and measure the menin-MLL interaction through physical and chemical properties. By using methods such as binding assays, structural analysis, and functional measurements, the invention translates the invisible molecular interaction into detectable signals, enabling identification and characterization of the target.
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.